Phenylpyrrolidinone formyl peptide 2 receptor agonists

ABSTRACT

The disclosure relates to compounds of Formulae (I)-(IX), which are formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPR1) receptor agonists. The disclosure also provides compositions and methods of using the compounds, for example, for the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to priority pursuant to 35 U.S.C. § 119(e)to U.S. provisional patent application No. 62/638,556, filed Mar. 5,2018, which is incorporated herein in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to novel pyrrolidinone compounds, whichare formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1(FPR1) receptor agonists, compositions containing them, and methods ofusing them, for example, for the treatment of atherosclerosis, heartfailure, chronic obstructive pulmonary disease (COPD), and relateddiseases.

Formyl peptide receptor 2 (FPR2) belongs to a small group ofseven-transmembrane domain, G protein-coupled receptors that areexpressed in multiple human tissues including immune cells and are knownto be important in host defense and inflammation. FPR2 sharessignificant sequence homology with FPR1 and FPR3 (Journal ofAutoimmunity 85, 2017, 64-77). Collectively, these receptors bind anumber of structurally diverse agonists, including N-formyl andnonformyl peptides which act as chemo attractants and activatephagocytes. The endogenous peptide Annexin A1 and its N-terminalfragments are examples of ligands that bind human FPR1 and FPR2. Fattyacids such as eicosanoid, lipoxin A4, which belongs to a class of smallpro-resolution mediators (SPMs), has also been identified as an agonistfor FPR2 (Ye R D., et al., Pharmacol. Rev., 2009, 61, 119-61).

Endogenous FPR2 pro-resolution ligands, such as lipoxin A₄ and AnnexinA1, have been reported to trigger a wide array of cytoplasmatic cascadessuch as Gi coupling, Ca²⁺ mobilization and β-arrestin recruitment. (IntJ Mol Sci. 2013 April; 14(4): 7193-7230). FPR2 regulates both innate andadaptive immune systems including neutrophils, macrophages, T-, andB-cells. In neutrophils, FPR2 ligands modulate movement, cytotoxicityand life span. In macrophages, agonism of FPR2 prevents apoptosis andenhances efferocytosis. (Chandrasekharan J A, Sharma-Walia N., J.Inflamm. Res., 2015, 8, 181-92). The initiation of resolution ofinflammation by FPR2 agonism is responsible for enhancing anti-fibroticwound healing and returning of the injured tissue to homeostasis (RomanoM., et al., Eur. J. Pharmacol., 2015, 5, 49-63).

Chronic inflammation is part of the pathway of pathogenesis of manyhuman diseases and stimulation of resolution pathways with FPR2 agonistsmay have both protective and reparative effects. Ischaemia-reperfusion(I/R) injury is a common feature of several diseases associated withhigh morbidity and mortality, such as myocardial infarction and stroke.Non-productive wound healing associated with cardiomyocyte death andpathological remodeling resulting from ischemia-reperfusion injury leadsto scar formation, fibrosis, and progressive loss of heart function.FPR2 modulation is proposed to enhance myocardial wound healing postinjury and diminish adverse myocardial remodeling (Kain V., et al., J.Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 pro-resolutionagonists, in the central nervous system, may be useful therapeutics forthe treatment of a variety of clinical IR conditions, including strokein brain (Gavins F N., Trends Pharmacol. Sci., 2010, 31, 266-76) and IRinduced spinal cord injury (Liu Z Q., et al., Int. J. Clin. Exp. Med.,2015, 8, 12826-33).

In addition to beneficial effects of targeting the FPR2 receptor withnovel pro-resolution agonists for treatment of I/R induced injurytherapeutic, utility of these ligands can also be applied to otherdiseases. In the cardiovascular system both the FPR2 receptor and itspro-resolution agonists were found to be responsible foratherogenic-plaque stabilization and healing (Petri M H., et al.,Cardiovasc. Res., 2015, 105, 65-74; and Fredman G., et al., Sci. Trans.Med., 2015, 7(275); 275ra20). FPR2 agonists also have been shown to bebeneficial in preclinical models of chronic inflammatory human diseases,including: infectious diseases, psoriasis, dermatitis, inflammatorybowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain,metabolic/diabetes diseases, cancer, COPD, asthma and allergic diseases,cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritisand other joint diseases, Alzheimer's disease, kidney fibrosis, andorgan transplantation (Romano M., et al., Eur. J. Pharmacol., 2015, 5,49-63, Perrett, M., et al., Trends in Pharm. Sci., 2015, 36, 737-755).

SUMMARY OF THE INVENTION

The present invention provides novel pyrrolidinone, and their analoguesthereof, which are useful as FPR2 agonists, including stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated with FPR2, suchas inflammatory diseases, heart diseases, chronic airway diseases,cancers, septicemia, allergic symptoms, HIV retrovirus infection,circulatory disorders, neuroinflammation, nervous disorders, pains,prion diseases, amyloidosis, and immune disorders. The heart diseasesare selected from the group consisting of angina pectoris, unstableangina, myocardial infarction, acute coronary disease, cardiaciatrogenic damage, and heart failure including, but not limited to,acute heart failure, chronic heart failure of ischemic and non-ischemicorigin, systolic heart failure, diastolic heart failure, heart failurewith reduced ejection fraction (HF_(R)EF), and heart failure withpreserved ejection fraction (HF_(P)EF).

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula (I), which are formylpeptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPR1)receptor agonists, compositions containing them, and methods of usingthem, for example, in the treatment of atherosclerosis, heart failure,chronic obstructive pulmonary disease (COPD), and related diseases.

One aspect of the invention is a compound of Formula (I):

wherein:

Ar¹ is phenyl, pyridinyl, or pyridazinyl and is substituted with 1 halo,haloalkyl or haloalkoxy substituent in the 4-position and 0-2 additionalhalo or haloalkyl substituents;

Ar² is phenyl or pyridinyl substituted with 0-2 substituents selectedfrom cyano, fluoro, alkyl, haloalkyl, cycloalkyl, alkoxy, andhaloalkoxy;

Ar³ is phenyl or pyridinyl and is substituted with 0-2 substituentsselected from cyano, halo, hydroxyalkyl, alkoxyalkyl, (R¹R²N)alkyl,(alkyl)₂(O)P, (alkyl)(O)(NR¹)S, alkylSO₂, and alkylSO₂NH;

R¹ is hydrogen or alkyl; and

R² is hydrogen or alkyl; or (R¹)(R²)N taken together is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl and issubstituted with 0-3 substituents selected from fluoro and alkyl; or apharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of Formula (I) where Ar¹is phenyl substituted with 1 halo, haloalkyl or haloalkoxy substituentin the 4-position and 0-2 additional halo or haloalkyl substituents.

Another aspect of the invention is a compound of Formula (I) where Ar²is phenyl substituted with 0 substituents, 1 alkyl or cycloalkylsubstituent, or 2 fluoro substituents.

Another aspect of the invention is a compound of Formula (I) where Ar²is phenyl substituted with 0 substituents or 2 fluoro substituents.

Another aspect of the invention is a compound of Formula (I) where Ar³is phenyl substituted with 1-2 substituents selected from cyano, halo,hydroxyalkyl, alkoxyalkyl, (R¹R²N)alkyl, (alkyl)₂(O)P, (alkyl)(O)(NR¹)S,alkylSO₂, and alkylSO₂NH.

Another aspect of the invention is a compound of Formula (I) where R¹ ishydrogen and R² is hydrogen.

Another aspect of the invention is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ is aryl substituted with 1-2 R^(1a) and 1-2 R^(1b) or monocyclicheteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, andsulfur, and substituted with 1-2 R^(1a) and 1-2 R^(1b);

Ar² is aryl substituted with 1-4 R^(2a) or 6-membered heteroaryl with1-2 nitrogen atoms, and substituted with 1-4 R^(2a);

Ar³ is aryl substituted with 1-4 R^(3a) or monocyclic heteroaryl with1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, andsubstituted with 1-4 R^(3a);

R^(1a) is hydrogen or halo;

R^(1b) is halo, haloalkyl, alkoxy, or haloalkoxy;

R^(2a) is hydrogen, cyano, halo, alkyl, hydroxyalkyl, haloalkyl,cycloalkyl, alkoxy, or haloalkoxy; alternatively, two adjacent R^(2a)groups are taken together with the carbon atoms to which they areattached to form a heterocycle with 1-4 heteroatoms selected fromnitrogen, oxygen, and sulfur;

R^(3a) is cyano, halo, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl,haloalkyl, (R¹R²N)alkyl, R¹R²N, alkylC(O)(R²)Nalkyl, (alkyl)₂(O)P,(alkoxy)₂(O)P, (alkoxy)(alkyl)(O)P, (alkyl)(O)(NR¹)S, alkylSO₂, oralkylSO₂NH; alternatively, two adjacent R^(3a) groups are taken togetherwith the carbon atoms to which they are attached to form a heterocyclewith 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur;

R^(4a) or R^(4b) is independently hydrogen, alkyl, alkoxy,hydroxylalkyl, alkoxyalkyl, or haloalkoxy; alternatively, R^(4a) andR^(4b) together with the carbon atom they are both attached to form aC₃₋₆ cycloalkyl;

R^(5a) or R^(5b) is independently hydrogen, alkyl, hydroxylalkyl,alkoxyalkyl or haloalkoxyl;

R¹ is hydrogen or alkyl; and

R² is hydrogen or alkyl; or R¹R²N taken together is azetidinyl, oxazolylpyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and issubstituted with 0-3 substituents selected from halo, alkyl, and oxo.

Another aspect of the invention is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ is phenyl substituted with 1-2 R^(1a) and 1-2 R^(1b) or 6-memberedheteroaryl with 1-3 nitrogen atoms and substituted with 1R^(1a) and 1-2R^(1b);

Ar³ is phenyl substituted with 1-3 R^(3a) or 5- to 6-membered heteroarylwith 1-3 nitrogen atoms and substituted with 1-3 R^(3a);

R^(1a) is hydrogen or halo;

R^(1b) is halo, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy;

R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy;

R^(3a) is cyano, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxyalkyl,C₁₋₄ haloalkyl, (R¹R²N)C₁₋₄ alkyl, R¹R²N, C₁₋₄ alkylC(O)(R²)NC₁₋₄ alkyl,(C₁₋₄ alkyl)₂(O)P, (C₁₋₄ alkoxy)₂(O)P, (C₁₋₄ alkoxy)(C₁₋₄ alkyl)(O)P,C₁₋₄ alkylSO₂, or C₁₋₄ alkylSO₂NH;

R¹R²N taken together is oxazolyl or pyrrolidinyl and is substituted with0-3 substituents selected from halo, alkyl, and oxo;

R^(4a) or R^(4b) is independently hydrogen, C₁₋₄ alkyl, or C₁₋₄hydroxylalkyl; alternatively, R^(4a) and R^(4b) together with the carbonatom they are both attached to form a C₃₋₆ cycloalkyl; and

R^(5a) or R^(5b) is independently hydrogen, C₁₋₄ alkyl, C₁₋₄hydroxylalkyl, or C₁₋₄ alkoxyalkyl.

Another aspect of the invention is a compound of Formula (II) or (III),or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ is phenyl substituted with 1-2 R^(1a) and 1-2 R^(1b), pyridinylsubstituted with 1 R^(1a) and 1-2 R^(1b), or pyrazinyl substituted with1R^(1a) and 1-2 R^(1b); and

Ar³ is phenyl substituted with 1-3 R^(3a), pyrazolyl substituted with1-3 R^(3a), pyridinyl substituted with 1-3 R^(3a), or pyrimidinylsubstituted with 1-3 R^(3a).

Another aspect of the invention is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ is phenyl substituted with 1-2 R^(1a) and 1-2 R^(1b), pyridinylsubstituted with 1 R^(1a) and 1-2 R^(1b), or pyrazinyl substituted with1 R^(1a) and 1-2 R^(1b);

R^(1a) is hydrogen or halo;

R^(1b) is halo, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy;

R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy;

R^(3a) is cyano, halo, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ alkoxyalkyl,C₁₋₃ haloalkyl, R¹R²N, (C₁₋₃ alkyl)₂(O)P, (C₁₋₃ alkoxy)₂(O)P, (C₁₋₃alkoxy)(C₁₋₃ alkyl)(O)P, C₁₋₃ alkylSO₂, or C₁₋₃ alkylSO₂NH;

R^(4a) or R^(4b) is independently hydrogen, C₁₋₃ alkyl, or C₁₋₃hydroxylalkyl; alternatively, R^(4a) and R^(4b) together with the carbonatom they are both attached to form a C₃₋₆ cycloalkyl; and

R^(5a) or R^(5b) is independently hydrogen, C₁₋₃ alkyl, C₁₋₃hydroxylalkyl, or C₁₋₃ alkoxyalkyl.

Another aspect of the invention is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is hydrogen or F;

R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy;

R^(2a) is hydrogen, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or C₃₋₆cycloalkyl;

R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH; and

R^(3a′) is halo.

Another aspect of the invention is a compound of Formula (V), or apharmaceutically acceptable salt thereof, wherein:

R^(1a) is hydrogen or F;

R^(1b) is F, Cl, or CF₃;

R^(2a) is hydrogen, F, Cl, isopropyl, CF₃, or cyclopropyl;

R^(3a) is (CH₃)₂(O)P, (CH₃CH₂)₂(O)P, (CH₃CH₂O)(CH₃)(O)P, CH₃SO₂, orCH₃SO₂NH; and

R^(3a′) is F.

Another aspect of the invention is a compound of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is hydrogen or halo;

R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy;

R^(2a) is hydrogen, halo, C₁₋₃ alkyl, or C₃₋₆ cycloalkyl;

R^(3a) is (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

Another aspect of the invention is a compound of Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

Ar³ is pyrazolyl substituted with 1-3 R^(3a), pyridinyl substituted with1-3 R^(3a), or pyrimidinyl substituted with 1-3 R^(3a);

R^(1a) is hydrogen or halo;

R^(1b) is halo, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy;

R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy;

R^(3a) is cyano, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxyalkyl,(R¹R²N)C₁₋₄ alkyl, R¹R²N—, (C₁₋₄ alkyl)₂(O)P, (C₁₋₄ alkoxy)₂(O)P, (C₁₋₄alkoxy)(C₁₋₄ alkyl)(O)P, C₁₋₄ alkylSO₂, or C₁₋₄ alkylSO₂NH;

R¹ is hydrogen or alkyl;

R² is hydrogen or alkyl; or R¹R²N taken together is oxazolyl orpyrrolidinyl, and is substituted with 0-3 substituents selected fromhalo, alkyl, or oxo;

R^(4a) or R^(4b) is independently hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkoxyalkyl, or C₁₋₄ haloalkoxy; R^(4a) and R^(4b) together withthe carbon atom to which they are both attached form a C₃₋₆ cycloalkyl;and

R^(5a) or R^(5b) is independently hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkoxyalkyl, or C₁₋₄ haloalkoxy.

Another aspect of the invention is a compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is hydrogen or halo;

R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy;

R^(2a) is hydrogen, halo, C₁₋₃ alkyl, or C₃₋₆ cycloalkyl;

R^(3a) is (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂alkyl)(O)P, Cl₂ alkylSO₂, or C₁₋₂ alkylSO₂NH; and

R^(5a) or R^(5b) is independently hydrogen or C₁₋₂ alkyl.

Another aspect of the invention is a compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a) is hydrogen or halo;

R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy;

R^(2a) is hydrogen, halo, C₁₋₂ haloalkyl, C₁₋₃ alkyl, or C₃₋₆cycloalkyl; Ar³ is

R^(3a) is (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, or C₁₋₂alkylSO₂NH;

R^(3a′) is halo;

R^(4a) or R^(4b) is independently hydrogen, C₁₋₂ alkyl, or C₁₋₂hydroxyalkyl; or R^(4a) and R^(4b) together with the carbon atom towhich they are both attached form a C₃₋₆ cycloalkyl; and

R^(5a) or R^(5b) is independently hydrogen, C₁₋₂ alkyl, C₁₋₂hydroxyalkyl, or C₁₋₂ alkoxyalkyl.

Another aspect of the invention is a compound of Formula (II), (III),(IV), (VII), or (IX), or a pharmaceutically acceptable salt thereof,wherein:

R^(4a) is hydrogen;

R^(4b) is hydrogen;

R^(5a) is C₁₋₂ alkyl, C₁₋₂ hydroxylalkyl, or C₁₋₂ alkoxyalkyl; and

R^(5b) is hydrogen.

Another aspect of the invention is a compound of formula (II), (III),(IV), (VII), or (IX), or a pharmaceutically acceptable salt thereof,wherein:

R⁴a is C₁₋₂ alkyl;

R^(4b) is C₁₋₂ alkyl; or R^(4a) and R^(4b) are taken together to form acyclopropyl;

R^(5a) is hydrogen; and

R^(5b) is hydrogen.

Another aspect of the invention is a compound selected from the groupconsisting

For a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII),(VIII), or (IX), the scope of any instance of a variable substituent,including Ar¹, Ar², Ar³, R^(1a), R^(1b), R^(2a), R^(3a), R^(4a), R^(4b),R^(5a), R^(5b), R¹, R² can be used independently with the scope of anyother instance of a variable substituent. As such, the inventionincludes combinations of the different aspects.

In one non-limiting embodiment, for a compound of Formula (II), (III),(IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are all hydrogen;Ar¹ is phenyl, pyridinyl, or pyrazinyl, each substituted with 1R^(1a)and 1-2 R^(1b); R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂haloalkyl, or C₁₋₂ alkoxy; Ar² is phenyl substituted with 1-4 R^(2a);R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is phenyl,pyrazolyl, pyridinyl, or pyrimidinyl, each substituted with 1-4 R^(3a);R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is phenyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a)is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar²is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,or C₁₋₄ haloalkoxy; Ar³ is pyrazolyl substituted with 1-4 R^(3a); R^(3a)is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is phenyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a)is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar²is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,or C₁₋₄ haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a);R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is phenyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a)is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar²is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,or C₁₋₄ haloalkoxy; Ar³ is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl,each substituted with 1-4 R^(3a); R^(3a) is halo, hydroxyalkyl,alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b);R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen,halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is phenyl substituted with 1-4R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P,(C₁₋₂ alkoxy)₂(O)P, (C₁₋₂alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b);R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen,halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is pyrazolyl substituted with 1-4R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P,(C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, orC₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b);R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen,halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is pyridinyl substituted with 1-4R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P,(C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, orC₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b);R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen,halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P,(C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, orC₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyrazinyl substituted with 1R^(1a) and 1-2 R^(1b);R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen,halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is phenyl substituted with 1-4R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P,(C₁₋₂ alkoxy)₂(O)P, (C₁₋₂alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyrazinyl substituted with 1R^(1a) and 1-2 R^(1b);R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen,halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is pyrazolyl substituted with 1-4R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P,(C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, orC₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyrazinyl substituted with 1R^(1a) and 1-2 R^(1b);R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen,halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl,C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is pyridinyl substituted with 1-4R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P,(C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, orC₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a), R^(4b), R^(5a), R^(5b) are allhydrogen; Ar¹ is pyrazinyl substituted with 1R¹a and 1-2 R^(1b); R^(1a)is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar²is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,or C₁₋₄ haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a);R^(3a) is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH.

In one non-limiting embodiment, for a compound of Formula (II), (III),(IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; or R^(4a) ishydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is phenyl, pyridinyl, or pyrazinyl, each substituted with 1R^(1a) and1-2 R^(1b); R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl,or C₁₋₂ alkoxy; Ar² is phenyl substituted with 1-4 R^(2a); R^(2a) ishydrogen, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; Ar³ is phenyl, pyrazolyl,pyridinyl, or pyrimidinyl, each substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; orR^(4a) is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) aretaken together to form a cyclopropyl; R^(5a) and R^(5b) are allhydrogen; Ar¹ is phenyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a)is hydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar²is phenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,or C₁₋₄ haloalkoxy; Ar³ is pyrazolyl substituted with 1-4 R^(3a); R^(3a)is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is phenyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen orhalo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is phenyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen orhalo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, eachsubstituted with 1-4 R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl,(C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P,C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is phenyl substituted with 1-4 R^(3a); R^(3a) is halo,hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁-4 alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrazolyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁-4 alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyridinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyridinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyrazinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is phenyl substituted with 1-4 R^(3a); R^(3a) is halo,hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyrazinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁-4 alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrazolyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyrazinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyridinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) is methyl, R^(4b) is methyl; R^(4a)is hydrogen, R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) and R^(5b) are all hydrogen; Ar¹is pyrazinyl substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkyl SO₂NH.

In one non-limiting embodiment, for a compound of Formula (II), (III),(IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a) ishydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is phenyl, pyridinyl,or pyrazinyl, each substituted with 1R^(1a) and 1-2 R^(1b); R^(1a) ishydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² isphenyl substituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,or C₁₋₄ haloalkoxy; Ar³ is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl,each substituted with 1-4 R^(3a); R^(3a) is halo, hydroxyalkyl,alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is phenylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrazolyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is phenylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is phenylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, eachsubstituted with 1-4 R^(3a); R^(3a) is halo, hydroxyalkyl, alkoxyalkyl,(C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P,C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyridinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is phenyl substituted with 1-4 R^(3a); R^(3a) is halo,hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyridinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrazolyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyridinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyridinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyridinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyrazinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is phenyl substituted with 1-4 R^(3a); R^(3a) is halo,hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyrazinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrazolyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyrazinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyridinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In another non-limiting embodiment, for a compound of Formula (II),(III), (IV), (VII), or (IX), R^(4a) and R^(4b) are all hydrogen; R^(5a)is hydrogen, R^(5b) is methyl or hydroxymethyl; Ar¹ is pyrazinylsubstituted with 1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; Ar² is phenylsubstituted with 1-4 R^(2a); R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; Ar³ is pyrimidinyl substituted with 1-4 R^(3a); R^(3a) ishalo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P,(C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂ alkylSO₂NH.

In one preferred embodiment, for a compound of Formula (II), (III),(IV), or (VII), or (IX), R^(4a) is methyl; R^(4b) is methyl; R^(4a) ishydrogen; R^(4b) is hydroxymethyl; or R^(4a) and R^(4b) are takentogether to form a cyclopropyl; R^(5a) is hydrogen, R^(5b) is methyl orhydroxymethyl; R^(5a) is hydrogen; R^(5b) is hydrogen; or R^(4a),R^(4b), R^(5a), R^(5b) are all hydrogen; Ar¹ is phenyl substituted with1R^(1a) and 1-2 R^(1b); R^(1a) is hydrogen, or F; R^(1b) is F, Cl, orCF₃; Ar² is phenyl substituted with 1-2 R^(2a); R^(2a) is hydrogen, F,Cl, isopropyl, CF₃CF₃, cyclopropyl; Ar³ is phenyl or pyridinyl, eachsubstituted with 1-2 R^(3a); R^(3a) is F, (CH₃)₂(O)P, (CH₃CH₂)₂(O)P,(CH₃CH₂O)(CH₃)(O)P, CH₃SO₂, Or CH₃SO₂NH.

Unless specified otherwise, these terms have the following meanings.“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Alkynyl” means a straightor branched alkyl group composed of 2 to 6 carbons with at least onetriple bond. “Cycloalkyl” means a monocyclic ring system composed of 3to 7 carbons. Terms with a hydrocarbon moiety (e.g. alkoxy) includestraight and branched isomers for the hydrocarbon portion. “Halo”includes fluoro, chloro, bromo, and iodo. “Haloalkyl” and “haloalkoxy”include all halogenated isomers from monohalo to perhalo. “Aryl” means amonocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbonatoms, or a bicyclic fused ring system wherein one or both of the ringsis aromatic. Bicyclic fused ring systems consist of a phenyl group fusedto a four- to seven-membered aromatic or non-aromatic carbocyclic ring.Representative examples of aryl groups include but are not limited tophenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl. “Heteroaryl”means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromaticring system with 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur. Where a bonding attachment location is notspecified, the bonding may be attached at any appropriate location asunderstood by practitioners in the art. Combinations of substituents andbonding patterns are only those that result in stable compounds asunderstood by practitioners in the art. Parenthetic and multiparentheticterms are intended to clarify bonding relationships to those skilled inthe art. For example, a term such as ((R)alkyl) means an alkylsubstituent further substituted with the substituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric formsincluding the structure below with the indicated carbon. The inventionincludes all stereoisomeric forms of the compounds including enantiomersand diastereomers. Methods of making and separating stereoisomers areknown in the art. The invention includes all tautomeric forms of thecompounds. The invention includes atropisomers and rotational isomers.

The invention is intended to include all isotopes of atoms occurring inthe compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include deuterium and tritium. Isotopesof carbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of theinvention can generally be prepared by conventional techniques known tothose skilled in the art or by processes analogous to those describedherein, using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent otherwise employed. Such compounds may have avariety of potential uses, for example as standards and reagents indetermining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

Biological Methods

N-formyl peptide receptors (FPRs) are a family of chemo attractantreceptors that facilitate leukocyte response during inflammation. FPRsbelong to the seven-transmembrane G protein-coupled receptor superfamilyand are linked to inhibitory G-proteins (Gi). Three family members(FPR1, FPR2 and FPR3) have been identified in humans and arepredominantly found in myeloid cells with varied distribution and havealso been reported in multiple organs and tissues. After agonistbinding, the FPRs activate a multitude of physiological pathways, suchas intra cellular signaling transduction, Ca²⁺ mobilization andtranscription. The family interacts with a diverse set of ligands thatincludes proteins, polypeptides and fatty acid metabolites whichactivate both pro-inflammatory and pro-resolution downstream responses.FPR2 and FPR1 Cyclic Adenosine Monophosphate (cAMP) Assays were used tomeasure the activity of the compounds in this patent.

FPR2 and FPR1 Cyclic Adenosine Monophosphate (cAMP) Assays. A mixture offorskolin (5 μM final for FPR2 or 10 μM final for FPR1) and IBMX (200 μMfinal) were added to 384-well Proxiplates (Perkin-Elmer) pre-dotted withtest compounds in DMSO (1% final) at final concentrations in the rangeof 0.020 nM to 100 μM. Chinese Hamster Ovary cells (CHO) overexpressinghuman FPR1 or human FPR2 receptors were cultured in F-12 (Ham's) mediumsupplemented with 10% qualified FBS, 250 μg/ml zeocin and 300 μg/mlhygromycin (Life Technologies). Reactions were initiated by adding 2,000human FPR2 cells per well or 4,000 human FPR1 cells per well inDulbecco's PBS (with calcium and magnesium) (Life Technologies)supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixtures wereincubated for 30 min at room temperature. The level of intracellularcAMP was determined using the HTRF HiRange cAMP assay reagent kit(Cisbio) according to manufacturer's instruction. Solutions of cryptateconjugated anti-cAMP and d2 fluorophore-labelled cAMP were made in asupplied lysis buffer separately. Upon completion of the reaction, thecells were lysed with equal volume of the d2-cAMP solution and anti-cAMPsolution. After a 1-h room temperature incubation, time-resolvedfluorescence intensity was measured using the Envision (Perkin-Elmer) at400 nm excitation and dual emission at 590 nm and 665 nm. A calibrationcurve was constructed with an external cAMP standard at concentrationsranging from 1 μM to 0.1 pM by plotting the fluorescent intensity ratiofrom 665 nm emission to the intensity from the 590 nm emission againstcAMP concentrations. The potency and activity of a compound to inhibitcAMP production was then determined by fitting to a 4-parametriclogistic equation from a plot of cAMP level versus compoundconcentrations.

The examples disclosed below were tested in the FPR2 and FPR1 cAMP assaydescribed above and found having FPR2 and/or FPR1 agonist activity.Table 1 below lists EC₅₀ values in the FPR2 and FPR1 cAMP assaysmeasured for the following examples.

TABLE 1 hFPR2 cAMP2 hFPR1 cAMP Example EC₅₀ (μM) EC₅₀ (μM) 1 0.000430.20 2 0.0042 0.36 3 0.0011 0.22 4 0.00093 1.7 5 0.00068 0.23 6 0.00100.19 7 0.0021 0.14 8 0.0020 0.061 9 0.0021 0.031 10 0.0022 0.13 110.0026 0.29 12 0.0025 0.45 13 0.0065 2.5 14 0.0072 0.60 15 0.010 1.5 160.012 0.12 17 0.016 4.1 18 0.020 2.1 19 0.022 0.078 20 0.024 >10 210.031 0.39 22 0.033 1.5 23 0.0082 0.70 24 0.022 1.4 25 0.00053 0.26 260.00055 0.047 27 0.00050 0.11 28 0.0098 0.55 29 0.0070 0.19 30 0.000220.083 31 0.0040 0.43 32 0.00091 0.25 33 0.0011 0.47 34 0.0041 0.026 350.0086 0.052 36 0.0047 0.069 37 0.00140 0.17 38 0.0035 0.042 39 0.000580.057 40 0.0046 0.050 41 0.0036 0.50 42 0.0010 0.22 43 0.0033 0.12 440.043 0.45 45 0.0030 0.14 46 0.0048 0.093 47 0.0028 0.064 48 0.0037 0.1149 0.0056 3.4 50 0.014 0.64 51 0.0082 1.3 52 0.010 1.1 53 0.0078 2.7 540.0055 0.90 55 0.022 >10 56 0.0075 7.7 57 0.00095 1.0 58 0.0063 0.61 590.0017 0.14 60 0.0037 0.12 61 0.023 0.37 62 0.031 0.72 63 0.00567 4.4 640.0088 2.9 65 0.0012 2.6 66 0.0049 0.58 67 0.00248 1.3 68 0.00053 0.1569 0.022 5.0 70 0.000077 0.020 71 0.0021 1.28 72 0.00061 0.054 730.00089 0.17 74 0.0022 0.14 75 0.0034 1.18 76 0.0041 2.1 77 0.0012 0.07978 0.0012 0.045 79 0.039 >10 80 0.0014 0.086 81 0.00052 0.027 82 0.00250.78 83 0.00041 0.00099 84 0.0060 0.28 85 0.00062 0.0051 86 0.000850.021 87 0.0016 0.0012 88 0.0053 0.0049 89 0.0044 0.025 90 0.0051 1.4 910.0057 0.20 92 0.0083 0.22 93 0.012 0.78 94 0.0018 0.012 95 0.032 0.2096 0.0029 0.075 97 0.0072 0.11 98 0.0029 0.27 99 0.00079 0.24 100 0.00200.092 101 0.00066 0.0011 102 0.0017 0.57 103 0.00057 0.35 104 0.00520.049 105 0.0069 0.071 106 0.0031 0.0035 107 0.011 0.0058 108 0.00140.053 109 0.00044 0.39 110 0.0011 0.64 111 0.030 0.54 112 0.00027 0.39113 0.00039 0.59 114 0.00086 0.27 115 0.0012 0.055 116 0.00121 0.89 1170.013 0.084 118 0.017 0.32 119 0.014 0.19 120 0.00078 0.16 121 0.000300.0050 122 0.00081 0.61 123 0.0015 0.24 124 0.00079 0.76 125 0.000990.18 126 0.012 >10 127 0.018 0.92 128 0.0010 0.024 129 0.0024 0.019 1300.0057 3.0 131 0.0012 0.061 132 0.00048 0.028 133 0.15 >5 134 0.00251500 135 0.0029 720

Pharmaceutical Compositions and Methods of Use

The compounds of the present invention may be administered to mammals,preferably humans, for the treatment of a variety of conditions anddisorders associated with the FPR2 receptor such as Behcet's disease,Sweet disease, systemic lupus erythematosus (SLE), Wegener'sgranulomatosis, virus infection, diabetes, amputations, cancers,bacterial infection, physical external injuries, physical disordersincluding exposure to radiation, vasoconstriction, anaphylacticreactions, allergic reactions, rhinitis, shocks (endotoxic, hemorrhagic,traumatic, splanchnic ischemia, and circulatory shocks), rheumatoidarthritis, gout, psoriasis, benign prostatic hyperplasia, myocardialischemia, myocardial infarction, heart failure, brain injuries,pulmonary diseases, COPD, COAD, COLD, acute lung injury, acuterespiratory distress syndrome, chronic bronchitis, pulmonary emphysema,asthma (allergic asthma and non-allergic asthma), cystic fibrosis,kidney fibrosis, nephropathy, renal glomerular diseases, ulcerativecolitis, IBD, Crohn's disease, periodontitis, pains, Alzheimer'sdisease, AIDS, uveitic glaucoma, conjunctivitis, Sjoegren's syndrome,rhinitis, atherosclerosis, neuroinflammatory diseases including multiplesclerosis, stroke, sepsis, and the like.

Unless otherwise specified, the following terms have the statedmeanings. The term “subject” refers to any human or other mammalianspecies that could potentially benefit from treatment with a FPR2 and/orFPR1 agonist as understood by practioners in this field. Some subjectsinclude human beings of any age with risk factors for cardiovasculardisease. Common risk factors include age, sex, weight, family history,sleep apnea, alcohol or tobacco use, physical inactivity arrthymia orsigns of insulin resistance such as acanthosis nigricans, hypertension,dyslipidemia, or polycystic ovary syndrome (PCOS). The term “patient”means a person suitable for therapy as determined by practitioners inthe field. “Treating” or “treatment” cover the treatment of a patient orsubject as understood by practitioners in this field. “Preventing” or“prevention” cover the preventive treatment (i.e., prophylaxis and/orrisk reduction) of a subclinical disease-state in a patient or subjectaimed at reducing the probability of the occurrence of a clinicaldisease-state as understood by practitioners in this field. Patients areselected for preventative therapy based on factors that are known toincrease risk of suffering a clinical disease state compared to thegeneral population. “Therapeutically effective amount” means an amountof a compound that is effective as understood by practitioners in thisfield.

Another aspect of the invention are pharmaceutical compositionscomprising a therapeutically effective amount of a compound of Formulae(I)-(IX) in combination with a pharmaceutical carrier.

Another aspect of the invention are pharmaceutical compositionscomprising a therapeutically effective amount of a compound of Formulae(I)-(IX) in combination with at least one other therapeutic agent and apharmaceutical carrier.

“Pharmaceutical composition” means a composition comprising a compoundof the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, anti-bacterialagents, anti-fungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, L. V., Jr. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012).

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

Another aspect of the invention is a method for treating heart diseasecomprising administering a therapeutically effective amount of acompound of Formula (I) to a patient.

Another aspect of the invention is a method for treating heart diseasewherein the heart disease is selected from the group consisting ofangina pectoris, unstable angina, myocardial infarction, heart failure,acute coronary disease, acute heart failure, chronic heart failure, andcardiac iatrogenic damage.

It will be understood that treatment or prophylaxis of heart failure mayinvolve treatment or prophylaxis of a cardiovascular event as well.Treatment or prophylaxis as referred to herein may refer to treatment orprophylaxis of certain negative symptoms or conditions associated withor arising as a result of a cardiovascular event. By way of example,treatment or prophylaxis may involve reducing or preventing negativechanges in fractional shortening, heart weight, lung weight, myocytecross sectional area, pressure overload induced cardiac fibrosis, stressinduced cellular senescence, and/or cardiac hypertrophy properties, orany combination thereof, associated with or arising as a result of acardiovascular event. Treatment may be administered in preparation foror in response to a cardiovascular event to alleviate negative effects.Prevention may involve a pro-active or prophylactic type of treatment toprevent the cardiovascular event or to reduce the onset of negativeeffects of a cardiovascular event.

In one embodiment, the present invention provides the use of compoundsof Formulae (I)-(IX) or a pharmaceutically acceptable salt thereof forthe preparation of a pharmaceutical composition for the treatment orprophylaxis of heart failure, for example, heart failure results fromhypertension, an ischemic heart disease, a non-ischemic heart disease,exposure to a cardiotoxic compound, myocarditis, Kawasaki's disease,Type I and Type II diabetes, thyroid disease, viral infection,gingivitis, drug abuse, alcohol abuse, pericarditis, atherosclerosis,vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy,myocardial infarction, atrial fibrosis, left ventricular systolicdysfunction, left ventricular diastolic dysfunction, coronary bypasssurgery, pacemaker implantation surgery, starvation, an eating disorder,muscular dystrophies, and a genetic defect. Preferably, the heartfailure to be treated is diastolic heart failure, heart failure withreduced ejection fraction (HF_(R)EF), heart failure with preservedejection fraction (HF_(P)EF), acute heart failure, and chronic heartfailure of ischemic and non-ischemic origin.

In one embodiment, the present invention provides the use of compoundsof Formulae (I)-(IX) to treat systolic and/or diastolic dysfunction,wherein the compound is administered in a therapeutically effectiveamount to increase the ability of the cardiac muscle cells to contractand relax thereby increasing the filling and emptying of both the rightand left ventricles, preferably, the left ventricle.

In another embodiment, the present invention provides the use ofcompounds of Formulae (I)-(IX) to treat heart failure wherein thecompound is administered in a therapeutically effective amount toincrease ejection fraction in the left ventricle.

In still another embodiment, the present invention provides the use ofcompounds of Formulae (I)-(IX) to treat heart failure wherein thecompound is administered in a therapeutically effective amount to reducefibrosis in heart tissue.

Another aspect of the invention is a method for treating heart diseasewherein the treatment is post myocardial infarction.

Another aspect of the invention is a method for treating dermatologicaldiseases including, but not limited to, rosacea, rosacea fulminans,sunburn, psoriasis, menopause-associated hot flashes, flushing andredness associated with hot flashes, erythema associated with hotflashes, hot flashes resulting from orchiectomyatopic dermatitis,treatment of redness and itch from insect bites, photoaging, seborrheicdermatitis, acne, allergic dermatitis, telangiectasia (dilations ofpreviously existing small blood vessels) of the face, angioectasias,rhinophyma (hypertrophy of the nose with follicular dilation), acne-likeskin eruptions (may ooze or crust), burning or stinging sensation,erythema of the skin, cutaneous hyperactivity with dilation of bloodvessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome, localitching and discomfort associated with hemorrhoids, hemorrhoids,erythema multiforme minor, erythema multiforme major, erythema nodosum,eye puffiness, urticaria, pruritis, purpura, varicose veins, contactdermatitis, atopic dermatitis, nummular dermatitis, generalizedexfoliative dermatitis, stasis dermatitis, lichen simplex chronicus,perioral dermatitis, pseudofolliculitis barbae, granuloma annulare,actinic keratosis, basal cell carcinoma, squamous cell carcinoma,eczema, dermal wound healing, hypertrophic scars, keloids, burns,rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis,actinic keratoses, basal cell carcinoma, squamous cell carcinoma,melanoma, viral warts, photoaging, photodamage, melasma,post-inflammatory hyperpigmentation, other disorders of pigmentation,and alopecia (scarring and non-scarring forms). The compounds belowwould be expected to have therapeutic effects in many different types ofskin disease, but have been exemplified by demonstrating acceleratedwound healing activity.

Another aspect of the invention is a method for treating heart diseasecomprising administering a therapeutically effective amount of acompound of Formula (I) to a patient in conjunction with othertherapeutic agents.

The compounds of this invention can be administered by any suitablemeans, for example, orally, such as tablets, capsules (each of whichincludes sustained release or timed release formulations), pills,powders, granules, elixirs, tinctures, suspensions (includingnanosuspensions, microsuspensions, spray-dried dispersions), syrups, andemulsions; sublingually; bucally; parenterally, such as by subcutaneous,intravenous, intramuscular, or intrasternal injection, or infusiontechniques (e.g., as sterile injectable aqueous or non-aqueous solutionsor suspensions); nasally, including administration to the nasalmembranes, such as by inhalation spray; topically, such as in the formof a cream or ointment; or rectally such as in the form ofsuppositories. They can be administered alone, but generally will beadministered with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.01 to about 5000 mg per day, preferably between about 0.1 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition. Atypical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule. A typical injectablepreparation is produced by aseptically placing at least one of thecompounds of the present invention (250 mg) into a vial, asepticallyfreeze-drying and sealing. For use, the contents of the vial are mixedwith 2 mL of physiological saline, to produce an injectable preparation.

The compounds of the present invention may be employed in combinationwith other suitable therapeutic agents useful in the treatment of theaforementioned diseases or disorders including: anti-atheroscleroticagents, anti-dyslipidemic agents, anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thromboticagents, anti-retinopathic agents, anti-neuropathic agents,anti-nephropathic agents, anti-ischemic agents, anti-hypertensiveagents, anti-obesity agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, agents for treatingheart failure, agents for treating peripheral arterial disease, agentsfor treating malignant tumors, and anti-inflammatory agents.

The compounds of the invention may be used with at least one of thefollowing heart failure agents selected from loop diuretics, Angiotensinconverting enzyme (ACE) inhibitors, Angiotensin II receptor blockers(ARBs), angiotensin receptor-neprilysin inhibitors (ARNI), betablockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1agonists, APJ agonists and cardiotonic agents. These agents include, butare not limited to furosemide, bumetanide, torsemide,sacubitrial-valsartan, thiazide diruetics, captopril, enalapril,lisinopril, carvedilol, metopolol, bisoprolol, serelaxin,spironolactone, eplerenone, ivabradine, candesartan, eprosartan,irbestarain, losartan, olmesartan, telmisartan, and valsartan.

The compounds of the present invention may be employed in combinationwith at least one of the following therapeutic agents in treatingatherosclerosis: anti-hyperlipidemic agents, plasma HDL-raising agents,anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors), LXR agonist, probucol,raloxifene, nicotinic acid, niacinamide, cholesterol absorptioninhibitors, bile acid sequestrants (such as anion exchange resins, orquaternary amines (e.g., cholestyramine or colestipol)), low densitylipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate,cipofibrate, gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidantvitamins, β-blockers, anti-diabetes agents, angiotensin II antagonists,angiotensin converting enzyme inhibitors, platelet aggregationinhibitors, fibrinogen receptor antagonists, aspirin and fibric acidderivatives.

The compounds of the present invention may be employed in combination atleast one of the following therapeutic agents in treating cholesterolbiosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor.Examples of suitable HMG-CoA reductase inhibitors include, but are notlimited to, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, and rosuvastatin.

The compounds of the invention may be used in combination with at leastone of the following anti-diabetic agents depending on the desiredtarget therapy. Studies indicate that diabetes and hyperlipidemiamodulation can be further improved by the addition of a second agent tothe therapeutic regimen. Examples of anti-diabetic agents include, butare not limited to, sulfonylureas (such as chlorpropamide, tolbutamide,acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride,and glipizide), biguanides (such as metformin), thiazolidinediones (suchas ciglitazone, pioglitazone, troglitazone, and rosiglitazone), andrelated insulin sensitizers, such as selective and non-selectiveactivators of PPARα, PPARβ and PPARγ; dehydroepiandrosterone (alsoreferred to as DHEA or its conjugated sulphate ester, DHEA-SO₄);anti-glucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4)inhibitor (such as sitagliptin, saxagliptin), GLP-1 agonists or analogs(such as exenatide), α-glucosidase inhibitors (such as acarbose,miglitol, and voglibose), pramlintide (a synthetic analog of the humanhormone amylin), other insulin secretagogues (such as repaglinide,gliquidone, and nateglinide), insulin, as well as the therapeutic agentsdiscussed above for treating atherosclerosis.

The compounds of the invention may be used in combination with at leastone of the following anti-obesity agents selected fromphenylpropanolamine, phentermine, diethylpropion, mazindol,fenfluramine, dexfenfluramine, phentiramine, β₃-adrenoreceptor agonistagents; sibutramine, gastrointestinal lipase inhibitors (such asorlistat), and leptins. Other agents used in treating obesity orobesity-related disorders include neuropeptide Y, enterostatin,cholecytokinin, bombesin, amylin, histamine H₃ receptors, dopamine D₂receptor modulators, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the FPR2. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving FPR2 activity. For example, a compound of the presentinvention could be used as a reference in an assay to compare its knownactivity to a compound with an unknown activity. This would ensure theexperimenter that the assay was being performed properly and provide abasis for comparison, especially if the test compound was a derivativeof the reference compound. When developing new assays or protocols,compounds according to the present invention could be used to test theireffectiveness. The compounds of the present invention may also be usedin diagnostic assays involving FPR2.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of dyslipidemias and the sequelae thereof.In another embodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment of dyslipidemias and thesequelae thereof. The article of manufacture can further comprise: (d) asecond container, wherein components (a) and (b) are located within thesecond container and component (c) is located within or outside of thesecond container. Located within the first and second containers meansthat the respective container holds the item within its boundaries. Thefirst container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product. The second container is one used to hold thefirst container and, optionally, the package insert. Examples of thesecond container include, but are not limited to, boxes (e.g., cardboardor plastic), crates, cartons, bags (e.g., paper or plastic bags),pouches, and sacks. The package insert can be physically attached to theoutside of the first container via tape, glue, staple, or another methodof attachment, or it can rest inside the second container without anyphysical means of attachment to the first container. Alternatively, thepackage insert is located on the outside of the second container. Whenlocated on the outside of the second container, it is preferable thatthe package insert is physically attached via tape, glue, staple, oranother method of attachment. Alternatively, it can be adjacent to ortouching the outside of the second container without being physicallyattached. The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Chemistry Methods

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “aq” foraqueous, “Col” for column, “eq” for equivalent or equivalents, “g” forgram or grams, “mg” for milligram or milligrams, “L” for liter orliters, “mL” for milliliter or milliliters, “μL” for microliter ormicroliters, “N” for normal, “M” for molar, “nM” for nanomolar, “mol”for mole or moles, “mmol” for millimole or millimoles, “min” for minuteor minutes, “h” for hour or hours, “rt” for room temperature, “RT” forretention time, “ON” for overnight, “atm” for atmosphere, “psi” forpounds per square inch, “conc.” for concentrate, “aq” for “aqueous”,“sat” or “sat'd” for saturated, “MW” for molecular weight, “mw” or“awave” for microwave, “mp” for melting point, “Wt” for weight, “MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “a”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

Ac acetic AcOH acetic acid Acn (or MeCN) acetonitrile BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BISPINais(pinacolato)diboron Bn benzyl Boc tert-butyl carbonyl Boc₂Odi-tert-butyl dicarbonate Bu butyl dba as in (Pd₂(dba)₃)dibenzylideneacetone DCM dichloromethane DEAD diethyl azodicarboxylateDIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMAP4-dimethylaminopyridine DME dimethoxyethane DMF dimethylformamide DMSOdimethyl sulfoxide dppf 1,1′-bis(diphenylphosphino)ferrocene Et ethylEtOH ethanol EtOAc ethyl acetate HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetra- methyluroniumhexafluorophosphate HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate i-Bu isobutyl i-Pr isopropyl LAH lithiumaluminum hydride Me methyl MeOH methanol NBS N-bromosuccinimide NMMN-methylmorpholine NMP N-Methylpyrrolidone Pet petroleum Ph phenyl Prpropyl rt room temperature t-Bu tert-butyl TBDMS-Clt-butyldimethylchlorosilane TEA triethylamine TFA trifluoroacetic acidTHF tetrahydrofuran Ts tosyl Xantphos4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

The disclosed compounds can be made by various methods known in the artincluding those of the following schemes and in the specific embodimentssection. The structure numbering and variable numbering shown in thesynthetic schemes are distinct from and should not be confused with thestructure or variable numbering in the claims or the rest of thespecification. The variables in the schemes are meant only to illustratehow to make some of the compounds of this invention.

The disclosure is not limited to the foregoing illustrative examples andthe examples should be considered in all respects as illustrative andnot restrictive, and all changes which come within the meaning and rangeof equivalency of the claims are therefore intended to be embraced.

A consideration in the planning of any synthetic route in this field isthe choice of the protecting group used for protection of the reactivefunctional groups present in the compounds described in this invention.An authoritative account describing the many alternatives to the trainedpractitioner is Greene, T. W. et al., Protecting Groups in OrganicSynthesis, 4th Edition, Wiley (2007)).

Compounds having the general Formula (I): wherein A, B, C, R^(x), R^(y),and R^(z) are defined above as Ar¹, Ar² and Ar³, (R^(2a))₁₋₄,(R^(3a))₁₋₄, and (R^(1a))₁₋₂, (R^(1b))₁₋₂, respectively, can be preparedby the following one or more of the synthetic Schemes.

1-Arylpyrrolidinone compounds of this invention wherein rings A, B and Care substituted phenyl rings can be prepared by the general route shownin Scheme 1, starting from a suitably protected 3-aminopyrrolidin-2-one1a, where PG is a protecting group such as Boc or Cbz. 1a can beprepared with methods known to one skilled in the art. Copper orPd-catalyzed coupling of 1a to a substituted iodobenzene or bromobenzene1b or other suitable halo aryl or heteroaryl compound in a suitablesolvent such as butanol or dioxane or toluene, in the presence of a basesuch as potassium carbonate or cesium carbonate and a suitable ligandsuch as N,N′-dimethylethylenediamine, or xanthphos can afford1-phenylpyrrolidinones 1c. Additional methods for this transformationinclude other variations of Ullmann, Goldberg, and Buchwaldcopper-catalyzed amidation or Buchwald Pd-catalyzed amidation dependingon the nature of ring B, using methods known to one skilled in the artfor these types of couplings (see for example Yin & Buchwald OrganicLett. 2000, 2, 1101; Klapers et al. JACS, 2001, 123, 7727; Klapars etal. JACS, 2002, 124, 7421; Yin & Buchwald JACS. 2002, 124, 6043;Kiyomor, Madoux & Buchwald, Tet. Lett., 1999, 40, 2657). Subsequentpalladium-catalyzed coupling of 1c to a suitably substituted phenylboronic acid 1d, or analogous boronate or trifluoroborate reagent, canprovide the biaryl compound 1e. Removal of the Boc or Cbz protectinggroup from 1e, followed by condensation of the resulting free amine witha suitably substituted phenyl isocyanate, 1 g or phenylcarbamate 1h canprovide ureas 1f. Suitable isocyanates or 4-nitrophenylcarbamates areeither commercially available or can be readily obtained from thecorresponding aniline by methods known to one skilled in the art.Alternately, the ureas 1f can be obtained by treatment of thedeprotected 3-aminopyrrolidinone intermediate with4-nitrophenylchloroformate to form the carbamate, followed bycondensation with an appropriately substituted aniline 1j. It will alsobe recognized by one skilled in the art that additional compounds ofthis invention wherein rings A, B or C are heteroaryl rings, such aspyridine, pyrimidine, thiazole, etc., can also be prepared using themethods outlined in Scheme 1 by substituting the appropriate heteroaryliodide or bromide for 1b, heteroarylboronic acid or boronate for 1d andheteroaryl amine, isocyanate or p-nitrophenylcarbamate for 1e. Racemiccompounds were separated using either chiral HPLC or SFC to providesingle enantiomers.

Alternatively as described in Scheme 2, compounds of this invention canbe prepared from intermediate 1c by first deprotecting the amine andforming the urea linkage to ring A using the conditions described abovefor the conversion of 1e to 1f to provide compounds 2a. Compound 2a canthen be coupled with an appropriate boronic acid or boronate underPd-catalysis conditions as shown in Scheme 1 for the transformation of1c to 1e. Racemic compounds can be separated using either chiral HPLC orSFC to provide single enantiomers.

Additionally as shown in Scheme 3, compounds of this invention can beprepared from intermediate 2a by conversion to boronate 3a usingiridium/Pd-catalyzed C—H borylation according to the methods of Suzukiand Miyaura followed by coupling of the resulting pinacolatoboronspecies with aryl or heteroaryl halides using palladium or coppercatalyzed processes to provide compounds 1f. Racemic compounds can beseparated using either chiral HPLC or SFC to provide single enantiomers.

Alternatively as described in Scheme 4, compounds of this invention canbe prepared by brominating amine 4a to give intermediate 4b. Subsequentamide coupling with 2,4-dibromo-butyryl chloride under basic conditionssuch as potassium phosphate in acetronitrile, followed by aqueousammonia mediated ring closure can give lactam 1c. Intermediate 1c can beconverted into final products using the reactions shown in Schemes 1-3.Racemic compounds can be separated using either chiral HPLC or SFC toprovide single enantiomers.

As described in Scheme 5, compounds of this invention with substitutedlactams can be prepared from intermediate 5a. Copper or Pd-catalyzedcoupling of 5a to a substituted iodobenzene or bromobenzene 1b or othersuitable halo aryl or heteroaryl compound in a suitable solvent such asbutanol or dioxane or toluene, in the presence of a base such aspotassium carbonate or cesium carbonate and a suitable ligand such asN,N′-dimethylethylenediamine, or Xanthphos can afford1-phenylpyrrolidinones 5b. Additional methods for this transformationinclude other variations of Ullmann, and Buchwald copper-catalyzedamidation or Buchwald Pd-catalyzed amidation depending on the nature ofring B, using methods known to one skilled in the art for these types ofcouplings. Subsequent preparation of a lithium lactam enolate andtreatment with an azide such as trisyl azide can yield intermediate 5c(see for example J. Org. Chem. 2003, 68, 7219-7233). Reduction of azideto amine followed by protection of amine can give intermediate 5d.Chemistry described in previous schemes can used to convert thisintermediate into compounds claimed in this patent. Racemic compoundscan be separated using either chiral HPLC or SFC to provide singleenantiomers.

Compounds of the invention can also be synthesized using the route shownin Scheme 6. Palladium catalyzed borylation of intermediate 1c givesintermediate 6a. Palladium mediated coupling of a suitiably substitutedaryl halides such as 6b can give biaryl lactam 1e. Chemistry describedin previous schemes can used to convert this intermediate into compoundsclaimed in this patent. Racemic compounds can be separated using eitherchiral HPLC or SFC to provide single enantiomers.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

The following methods were used in the exemplified Examples, exceptwhere noted otherwise. Purification of intermediates and final productswas carried out via either normal or reverse phase chromatography.Normal phase chromatography was carried out using prepacked SiO₂cartridges eluting with either gradients of hexanes and ethyl acetate orDCM and MeOH unless otherwise indicated. Reverse phase preparative HPLCwas carried out using C18 columns with UV 220 nm or prep LCMS detectioneluting with gradients of Solvent A (90% water, 10% MeOH, 0.1% TFA) andSolvent B (10% water, 90% MeOH, 0.1% TFA) or with gradients of Solvent A(95% water, 5% Acn, 0.1% TFA) and Solvent B (5% water, 95% ACN, 0.1%TFA) or with gradients of Solvent A (95% water, 2% Acn, 0.1% HCOOH) andSolvent B (98% Acn, 2% water, 0.1% HCOOH) or with gradients of Solvent A(95% water, 5% Acn, 10 mM NH₄OAc) and Solvent B (98% ACN, 2% water, 10mM NH₄OAc) or with gradients of Solvent A (98% water, 2% Acn, 0.1%NH₄OH) and Solvent B (98% Acn, 2% water, 0.1% NH₄OH).

LC/MS Methods Employed in Characterization of Examples. Reverse phaseanalytical HPLC/MS was performed on a Waters Acquity system coupled witha Waters MICROMASS® ZQ Mass Spectrometer.

Method A: Linear gradient of 0 to 100% B over 3 min, with 0.75 min holdtime at 100% B;

UV visualization at 220 nm

Column: Waters BEH C18 2.1×50 mm

Flow rate: 1.0 mL/min

Solvent A: 0.1% TFA, 95% water, 5% Acn

Solvent B: 0.1% TFA, 5% water, 95% Acn

Method B: Linear gradient of 0 to 100% B over 3 min, with 0.75 min holdtime at 100% B;

UV visualization at 220 nm

Column: Waters BEH C18 2.1×50 mm

Flow rate: 1.0 mL/min

Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn

Solvent B: 10 mM ammonium acetate, 5% water, 95% Acn

Analytical HPLC: Methods Employed in Characterization of Examples

Method C: Ascentis Express C18, 2.1×50 mm, 2.7-μm particles; Solvent A:95% water, 5% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.1% TFA;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 1-minutehold at 100% B; Flow: 1.1 mL/min.

Method D: Ascentis Express C18, 2.1×50 mm, 2.7-μm particles; Solvent A:95% water, 5% Acn with 10 mM ammonium acetate; Solvent B: 95% Acn, 5%water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100%B over 3 minutes, then a 1-minute hold at 100% B; Flow: 1.1 mL/min.

Method E: Column-Kinetex C18, 75×3 mm, 2.6-μm particles; Solvent A: 98%water, 2% Acn with 10 mM ammonium acetate; Solvent B: 98% Acn, 2% waterwith 10 mM ammonium acetate; Temperature: 25° C.; Gradient: 20-100% Bover 4 minutes, then a 0.6-minute hold at 100% B; Flow: 1.0 mL/min;then, Gradient: 100-20% B over 0.4 minutes; Flow: 1.5 mL/min, UV 220 nm.

SFC and Chiral Purity Methods

Method I: Chiralpak AD-H, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, % Cosolvent: 40% {0.2% DEA IN IPA:Acn (1:1)}, Total Flow: 4.0 g/min, BackPressure: 100 bars, Temperature: 25° C., UV: 218 nm.

Method II: Chiralpak OD-H, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, %Co solvent: 40% {0.2% DEA IN IPA:Acn (1:1)}, Total Flow: 4.0 g/min, BackPressure: 104 bars, Temperature: 24.9° C., UV: 287 nm.

Method III: Chiralpak OJ-H, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, %Co solvent: 30% (0.3% DEA in Methanol), Total Flow: 4.0 g/min, BackPressure: 101 bars, Temperature: 23.6° C., UV: 272 nm.

Method IV: Chiralpak AS-H, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, %Co solvent: 40% (0.3% DEA in Methanol), Total Flow: 4.0 g/min, BackPressure: 102 bars, Temperature: 25.4° C., UV: 272 nm.

Method V: Chiralcel OJ-H, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, % Cosolvent: 40% (0.2% DEA in Methanol), Total Flow: 4.0 g/min, BackPressure: 102 bars, Temperature: 24.6° C., UV: 272 nm.

Method VI: Luxcellulose-2, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, %Co solvent: 35% (0.2% DEA in Methanol), Total Flow: 3.0 g/min, BackPressure: 101 bars, Temperature: 23.6° C., UV: 260 nm.

Method VII: Chiralcel AS-H, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, %Co solvent: 40% (0.2% DEA in Methanol), Total Flow: 4.0 g/min, BackPressure: 101 bars, Temperature: 24.4° C., UV: 270 nm.

Method VIII: Chiralpak IC, 250×4.6 mm, 5.0-μm particles; % CO2: 60%, %Co solvent: 40% (0.2% DEA in Methanol), Total Flow: 4.0 g/min, BackPressure: 101 bars, Temperature: 24.4° C., UV: 270 nm.

Method IX: Column: chiralpak IF (250×4.6 mm), 5 micron, mobile phase:0.2% DEA in ethanol, FLOW: 1.0 ml\min.

Method X: Column: LUX AMYLOSE 2 (250×4.6 mm), 5 micron, mobile phase:0.2% DEA in n-hexane:ethanol: 5:95, FLOW: 1.0 ml\min.

Method XI: Column: CHIRALCEL OD-H (250×4.6 mm), 5 micron, mobile phase:0.2% DEA in n-hexane:ethanol: 70:30, FLOW: 1.0 ml\min.

Method XII: Column: CHIRAL PAK ID 250×4.6 mm), 5 micron, mobile phase:0.1% DEA in Methanol, FLOW: 1.0 ml/min.

NMR Employed in Characterization of Examples. ¹H NMR spectra wereobtained with Bruker or JEOL® Fourier transform spectrometers operatingat frequencies as follows: ¹H NMR: 400 MHz (Bruker or JEOL®) or 500 MHz(Bruker or JEOL®). ¹³C NMR: 100 MHz (Bruker or JEOL®). Spectra data arereported in the format: chemical shift (multiplicity, couplingconstants, and number of hydrogens). Chemical shifts are specified inppm downfield of a tetramethylsilane internal standard (6 units,tetramethylsilane=0 ppm) and/or referenced to solvent peaks, which in ¹HNMR spectra appear at 2.49 ppm for CD₂HSOCD₃, 3.30 ppm for CD₂HOD, 1.94for CD₃CN, and 7.24 ppm for CHCl₃, and which in ¹³C NMR spectra appearat 39.7 ppm for CD₃SOCD₃, 49.0 ppm for CD₃OD, and 77.0 ppm for CDCl₃.All ¹³C NMR spectra were proton decoupled.

Intermediate 1: 3-Aminopyrrolidin-2-one

To a stirred solution of hexamethyldisilazane (11 mL, 523 mmol) in CH₃CN(100 mL) at rt was added a solution of DL-2,4-diaminobutyric aciddihydrochloride (10 g, 52 mmol) in Acn (100 mL). The resulting reactionmixture was heated to reflux for 40 h. Then, the crude reaction mixturewas poured into ice cold MeOH (400 mL), stirred at rt for 30 min andevaporated under reduced pressure. The resulting solid was dissolved inCH₂Cl₂ (700 mL), and the insoluble residue was removed by filtrationunder vacuum. Then, the filtrate was concentrated under reduced pressureto give 3-aminopyrrolidin-2-one (4.1 g, 41 mmol, 78% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.59 (br. s., 2H), 3.23-3.10 (m,1H), 3.09-3.03 (m, 2H), 2.23-2.22 (m, 1H), 1.70-1.57 (m, 1H).

Intermediate 2: tert-Butyl (2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of 3-aminopyrrolidin-2-one (4.0 g, 40 mmol) inmethanol-triethylamine (130 mL, 9:1) under argon atmosphere at rt, wasadded Boc-anhydride (9.6 mL, 41 mmol). The reaction mixture was stirredat rt overnight followed by heating toreflux for two hours. Then, thereaction mixture was cooled to rt and concentrated under reducedpressure. Ether (50 mL) was added to the crude residue and the solid wasfiltered through Buchner funnel to yield Intermediate 2 (4.0 g, 20 mmol,50% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.69 (br. s.,1H), 6.99 (d, J=8.0 Hz, 1H), 4.06-3.96 (m, 1H), 3.19-3.10 (m, 2H),2.29-2.19 (m, 1H), 1.89-1.76 (m, 1H), 1.35 (s, 9H).

Intermediate 3: tert-Butyl(1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of Intermediate 2 (1.0 g, 5.0 mmol) in 1,4-dioxane(10 mL), were added 1,4-dibromo-2,3-difluorobenzene (1.6 g, 6.0 mmol),and Cs₂CO₃ (3.3 g, 10 mmol). The reaction mixture was purged withnitrogen for 5 min and charged with Xantphos (0.29 g, 0.50 mmol) andPd₂(dba)₃ (0.23 g, 0.25 mmol). The reaction mixture was again purgedwith nitrogen for 3 min and heated at 120° C. for 16 h. The reactionmixture was cooled, filtered through a Celite pad, and the filtrate wasconcentrated under reduced pressure. The crude product was purifiedusing column chromatography (pet. ether-EtOAc) to yield Intermediate 3(1.1 g, 2.8 mmol, 47% yield) as brown solid. MS(ESI) m/z: 391.2 (M+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ 7.61-7.59 (m, 1H), 7.35-7.28 (m, 2H),4.39-4.28 (m, 1H), 3.82-3.64 (m, 2H), 2.42-2.31 (m, 1H), 2.10-1.97 (m,1H), 1.40 (s, 9H).

Intermediate 4: tert-Butyl(1-(2,3-difluoro-2′-(methylsulfonamido)-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

To a solution of Intermediate 3 (1.1 g, 2.1 mmol) in 1.4-dioxane-water(11 mL, 10:1) at rt, were added (2-(methylsulfonamido)phenyl)boronicacid (0.45 g, 2.1 mmol), and potassium phosphate, tribasic (0.74 g, 4.2mmol). The reaction mixture was purged with nitrogen for 5 min andcharged with PdCl₂(dppf)-CH₂Cl₂ (0.17 g, 0.21 mmol). The reactionmixture was again purged with nitrogen for 3 min and heated at 80° C.for 16 h. The reaction mixture was cooled and filtered through a Celitepad, and the filtrate was concentrated under reduced pressure. The crudeproduct was purified via column chromatography (pet. ether-EtOAc) togive Intermediate 4 (0.44 g, 0.91 mmol, 43% yield) as brown solid.MS(ESI) m/z: 482.2 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H),7.53-7.44 (m, 2H), 7.38-7.29 (m, 4H), 7.24-7.17 (m, 1H), 4.36-4.31 (m,1H), 3.86-3.69 (m, 2H), 2.90 (s, 3H), 2.41-2.37 (m, 1H), 2.10-2.02 (m,1H), 1.41 (s, 9H).

Intermediate 5:N-(4′-(3-Amino-2-oxopyrrolidin-1-yl)-2′,3′-difluoro-[1,1′-biphenyl]-2-yl)methanesulfonamidehydrochloride

To an ice cooled solution of Intermediate 4 (440 mg, 0.91 mmol) in1,4-dioxane (1 mL), was added 4 N HCl in 1,4-dioxane (4.6 mL, 1 mmol),and the reaction mixture was stirred at rt for 2 h. The solvent wasevaporated under reduced pressure. The gummy solid was triturated withdiethyl ether (20 ml×2) and dried to yield Intermediate 5 (350 mg, 0.84mmol, 92% yield) as a brown solid.

MS(ESI) m/z: 418.2 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 1H),8.71 (br. s., 3H), 7.55-7.47 (m, 2H), 7.45-7.24 (m, 4H), 4.33-4.25 (m,1H), 3.97-3.85 (m, 2H), 2.89 (s, 3H), 2.64-2.54 (m, 1H), 2.30-2.17 (m,1H).

Intermediate 6: tert-butyl (R)-(2-oxopyrrolidin-3-yl)carbamate

1-Propanephosphonic anhydride (50% in EtOAc, 210 mL, 340 mmol) was addedto a solution of Boc-D-2,4-diaminobutyric acid (50 g, 230 mmol) and TEA(96 mL, 690 mmol) in DCM (1500 mL) at 0° C. The reaction mixture wasstirred at rt overnight under nitrogen. The reaction mixture wasconcentrated in vacuo, and the crude product was purified by columnchromatography (MeOH/DCM). The product was recrystallized withEtOAc/pet. ether to obtain Intermediate 6 (32 g, 70 mmol, 70% yield) asa white solid. MS(ESI) m/z: 201.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆)δ=7.69 (s, 1H), 6.99 (br. d., J=9.0 Hz, 1H), 4.01 (q, J=9.0 Hz, 1H),3.17-3.09 (m, 2H), 2.28-2.19 (m, 1H), 1.90-1.75 (m, 1H), 1.39 (s, 9H).

Intermediate 7: tert-butyl(R)-(1-(2,3-difluoro-4-bromophenyl)-2-oxopyrrolidin-3-yl)carbamate

A reaction mixture of Intermediate 6 (20 g, 100 mmol),2,3-difluoro-1,4-dibromobenzene (14 g, 110 mmol), potassium phosphatetribasic (32 g, 150 mmol), and cuprous iodide (7.6 g, 40 mmol) in1,4-dioxane (250 mL) was purged with nitrogen for 5 min.N,N′-Dimethylethylenediamine (5.5 mL, 50 mmol) was added, and thereaction mixture was heated in a pressure tube at 65° C. for 12 h. Thereaction mixture was diluted with EtOAc, filtered through Celite, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (35% EtOAc in pet ether) and recrystallized(EtOAc/pet ether) to obtain Intermediate 7 (18 g, 39 mmol, 39% yield) asa white solid. MS(ESI) m/z: 439.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ=7.54(ddd, J=8.5, 6.3, 2.3 Hz, 1H), 7.09 (ddd, J=8.5, 6.3, 2.3 Hz, 1H), 5.16(br. s., 1H), 4.41-4.30 (m, 1H), 3.87 (m, 1H), 3.79-3.69 (m, 1H),2.85-2.73 (m, 1H), 2.17-2.05 (m, 1H), 1.48 (m, 9H).

Intermediate 8: (2-bromophenyl)dimethylphosphine oxide

In a pressure tube, a reaction mixture of 1-bromo-2-iodobenzene (2.3 mL,18 mmol), potassium phosphate tribasic (5.6 g, 27 mmol) and Xantphos(0.61 g, 1.1 mmol) in DMF (40 mL) was degassed with argon for 3 min.Dimethylphosphine oxide (1.7 g, 21 mmol), and PdOAc₂ (0.20 g, 0.88 mmol)were added. The mixture was degassed with argon, sealed and heated for16 h at 110° C. The reaction mixture was cooled to rt, filtered throughCelite and concentrated under reduced pressure. The crude product waspurified by column chromatography (CHCl₃/MeOH) to give Intermediate 8(2.1 g, 9.0 mmol, 51% yield). MS(ESI) m/z: 233.0 (M+H)⁺. ¹H NMR (300MHz, DMSO-d₆) δ=7.97 (ddd, J=11.9, 7.8, 2.0 Hz, 1H), 7.76 (ddd, J=7.8,3.9, 1.2 Hz, 1H), 7.65-7.44 (m, 2H), 1.83 (d, J=13.5 Hz, 6H).

Intermediate 9: tert-butyl(R)-(1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

A reaction mixture of Intermediate 7 (15 g, 38 mmol), Intermediate 8 (11g, 46 mmol), bispin (24 g, 96 mmol), and K₃PO₄ (24 g, 115 mmol) in1,4-dioxane (250 mL) was purged with argon for 5 min. PdCl₂(dppf)-CH₂Cl₂adduct (3.1 g, 3.8 mmol) was added and the mixture was again purged withargon and then stirred in a pressure tube at 105° C. for 24 h. Thereaction mixture was diluted with EtOAc, filtered through Celite, andconcentrated under reduced pressure. The crude product was purified viacolumn chromatography (5% MeOH in CHCl₃) to give Intermediate 9 (9.0 g,19 mmol, 51% 5 yield). MS(ESI) m/z: 465.4 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ=7.92 (ddd, J=12.8, 7.6, 1.3 Hz, 1H), 7.70-7.49 (m, 2H),7.41-7.23 (m, 4H), 4.54-4.23 (m, 1H), 3.87-3.70 (m, 2H), 2.44-2.37 (m,1H), 2.21-2.00 (m, 1H), 1.51 (br. d., J=13.1 Hz, 6H), 1.42 (s, 9H).

Intermediate 10:(R)-3-amino-1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-2-onehydrochloride

HCl (4 M in 1,4-dioxane, 200 mL, 800 mmol) was added to a stirredsolution of Intermediate 9 (34 g, 73 mmol) in 1,4-dioxane (500 mL) atrt. The reaction mixture was stirred for 3 h and concentrated underreduced pressure to yield Intermediate 10 (28 g, 70 mmol, 95% yield),which was used in the next synthetic step without further purification.MS(ESI) m/z: 365.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ=8.62 (br. s.,3H), 7.95-7.81 (m, 1H), 7.68-7.57 (m, 2H), 7.39-7.32 (m, 2H), 7.31-7.24(m, 1H), 4.33-4.19 (m, 1H), 3.94-3.84 (m, 2H), 2.61-2.53 (m, 1H),2.25-2.15 (m, 1H), 1.53 (d, J=13.1 Hz, 6H).

Intermediate 11: phenyl (4-chloro-2-fluorophenyl)carbamate

Phenyl chloroformate (20 mL, 160 mmol) was added slowly to a solution of4-chloro-2-fluoroaniline (19 mL, 170 mmol) and pyridine (35 mL, 430mmol) in DCM (250 mL) at 0° C. The reaction mixture was gradually warmedto rt and stirred for 12 h. The reaction mixture was quenched withwater. The mixture was extracted with DCM (3×200 mL). The combinedorganic layers were washed with 0.5 N HCl and 10% sodium bicarbonate,dried over sodium sulfate, and concentrated in vacuo. The solid wasstirred in pet ether (100 mL) for 15 min, filtered and dried to getIntermediate 11 (36 g, 40 mmol, 78% yield). ¹H NMR (300 MHz,CHLOROFORM-d) δ=10.22-9.99 (m, 1H), 7.73 (br. t., J=8.7 Hz, 1H), 7.52(dd, J=10.7, 2.1 Hz, 1H), 7.47-7.38 (m, 2H), 7.34-7.18 (m, 4H).

Intermediate 12: phenyl (2-fluoro-4-(trifluoromethyl)phenyl)carbamate

Phenyl chloroformate (4.5 mL, 36 mmol) was added slowly to a solution of2-fluoro-4-(trifluoromethyl) aniline (8.0 g, 45 mmol) and pyridine (9.0mL, 110 mmol) in DCM (80 mL) at 0° C. The reaction mixture was graduallywarmed to rt and stirred for 3 h. The reaction mixture was quenched withwater and the mixture was extracted with DCM (3×200 mL). The combinedorganic layers were washed with 0.5 N HCl and 10% sodium bicarbonate,dried over sodium sulfate, and concentrated in vacuo. The solid wasstirred in pet. ether (100 mL) for 15 min, filtered and dried to giveIntermediate 11 (9.0 g, 30 mmol, 67% yield). MS(ESI) m/z: 317.2(M+NH₄)⁻. ¹H NMR (300 MHz, CHLOROFORM-d) δ=10.43 (s, 1H), 8.04 (br. t.,J=8.1 Hz, 1H), 7.75 (br. d., J=10.9 Hz, 1H), 7.60 (br. d., J=8.6 Hz,1H), 7.52-7.38 (m, 2H), 7.36-7.21 (m, 3H).

Intermediate 13:(R)-1-(1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidin-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

HCl (4 M in dioxane, 32 mL, 130 mmol) was added dropwise to a solutionof Intermediate 7 (10 g, 26 mmol) in DCE (300 mL) at 0° C. The reactionmixture was stirred for 2 h at rt and concentrated under reducedpressure. The crude intermediate was dissolved in 1,4-dioxane (300 mL)and cooled to 0° C. DIEA (22 mL, 130 mmol) was added dropwise over aperiod of 10 min, Intermediate 12 (6.9 g, 23 mmol) was added, and themixture was stirred for 12 h at rt. The reaction mixture was filteredthrough Celite, and the filter plug was washed with EtOAc. The filtratewas dried over sodium sulfate and concentrated under reduced pressure.The crude product was purified by column chromatography (2% MeOH:DCM) toyield Intermediate 13(12 g, 24 mmol, 95% yield). MS(ESI) m/z: 496.0(M+H)⁺.

Intermediate 14:(R)-1-(1-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxopyrrolidin-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

A solution of Intermediate 13 (12 g, 24 mmol) and bispin (18 g, 73 mmol)in 1,4-dioxane (120 mL) was degassed with argon for 5 min.PdCl₂(dppf)-CH₂Cl₂ (4.0 g, 4.8 mmol) was added, and the reaction mixturewas slowly heated to 110° C. and stirred for 16 h. The mixture wasfiltered through Celite, and the plug was washed with EtOAc. Thefiltrate was dried over sodium sulfate and concentrated under reducedpressure to give Intermediate 14 (13 g, 24 mmol, 99% yield). MS(ESI)m/z: 544.2 (M+H)⁺.

Intermediate 15: (3-bromopyridin-2-yl)dimethylphosphine oxide

To a stirred solution of 3-bromo-2-iodopyridine (5.0 g, 18 mmol) in DMF(5 mL), were added dimethylphosphine oxide (1.7 g, 21 mmol), and K₃PO₄(4.1 g, 19 mmol). The reaction mixture was purged with nitrogen for 5min and charged with Xantphos (1.0 g, 1.8 mmol) and Pd(OAc)₂ (0.20 g,0.88 mmol). The reaction mixture was again purged with nitrogen for 3min and heated at 100° C. for 9 hours. The reaction mixture was filteredthrough Celite and concentrated under reduced pressure. The crudematerial was purified by column chromatography (5% MeOH—CHCl₃) to giveIntermediate 15 (2.7 g, 12 mmol, 66% yield) as a brown liquid. MS(ESI)m/z: 234.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=8.72 (d, J=4.8 Hz, 1H),8.23-8.20 (m, 1H), 7.53-7.49 (m, 1H), 1.66 (d, J=13.6 Hz, 6H).

Intermediate 16: (2-Bromo-6-fluorophenyl)dimethylphosphine oxide

To a stirred solution of 1-bromo-3-fluoro-2-iodobenzene (2.0 g, 6.7mmol) in 1,4-dioxane (15 mL), were added dimethylphosphine oxide (0.62g, 8.0 mmol), and K₃PO₄ (1.6 g, 7.3 mmol). The reaction mixture waspurged with nitrogen for 5 min and charged with Xantphos (0.39 g, 0.67mmol) and Pd₂(dba)₃ (0.30 g, 0.33 mmol). The reaction mixture was againpurged with nitrogen for 3 min and heated at 100° C. for 9 h. Thereaction mixture was filtered through Celite and concentrated underreduced pressure. The crude material was purified by columnchromatography (0-100% EtOAc-Hexane, followed by 3% MeOH—CHCl₃) to giveIntermediate 16 (0.33 g, 1.3 mmol, 20% yield) as a yellow solid. MS(ESI)m/z: 250.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=7.63 (d, J=8.0 Hz, 1H),7.52 (td, J=8.0, 6.0 Hz, 1H), 7.43-7.28 (m, 1H), 1.87 (d, J=16.6 Hz,3H), 1.86 (d, J=16.6 Hz, 3H).

Intermediate 17: diethylphosphine oxide

To a stirred solution of 2M ethylmagnesium bromide (330 mL, 650 mmol) inTHF at rt, was added diethyl phosphonate (30 g, 220 mmol) and themixture was stirred for additional 2 hours. Then, a cold solution ofK₂CO₃ (90 g, 650 mmol) in water (120 mL) was added and the reactionmixture was filtered through a Celite pad. The filtrate was concentratedunder reduced pressure and azeotroped with toluene (20 mL×3). The crudematerial was diluted with DCM (100 mL), filtered through a cotton bedand concentrated under reduced pressure to give Intermediate 17 (12 g,110 mmol, 52% yield) as a yellowish liquid. MS(ESI) m/z: 107.2 [M+H]⁺.

Intermediate 18: (2-Bromophenyl)diethylphosphine oxide

To a stirred solution of 1-bromo-2-iodobenzene (10 g, 35.3 mmol) in DMF(50 mL), were added diethylphosphine oxide (4.5 g, 42 mmol), and K₃PO₄(15 g, 71 mmol). The reaction mixture was purged with nitrogen for 5 minand charged with Xantphos (1.0 g, 1.8 mmol) and palladium (II) acetate(0.40 g, 1.8 mmol). The reaction mixture was again purged with nitrogenfor 3 min, heated to 100° C. and stirred for 16 h. The reaction mixturewas cooled, filtered through a Celite pad, and the filtrate wasconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (MeOH-EtOAc) to yield the Intermediate 18 (3.2 g,12 mmol, 35% yield) as a yellowish liquid. MS(ESI) m/z: 263.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ=8.05-7.94 (m, 1H), 7.79-7.68 (m, 2H), 7.64-7.48(m, 1H), 2.26-2.03 (m, 4H), 0.93 (td, J=17.4, 7.7 Hz, 6H).

Intermediate 19: Dimethyl (2-bromophenyl)phosphonate

To a stirred solution of 2-bromophenyl trifluoromethanesulfonate (2.0 g,6.6 mmol) in toluene (100 mL), were added dimethyl phosphonate (1.1 g,9.8 mmol), and DIEA (1.7 mL, 9.8 mmol). The reaction mixture was purgedwith nitrogen for 5 min and charged with1,3-bis(diphenylphosphino)propane (0.14 g, 0.33 mmol) and palladium (II)acetate (0.04 g, 0.17 mmol). The reaction mixture was again purged withnitrogen for 3 min and heated at 110° C. for 16 h. The reaction mixturewas cooled and filtered through a Celite pad, and the filtrate wasconcentrated under reduced pressure. The product was purified by flashchromatography (5-10% MeOH in chloroform) to yield Intermediate 19 (1.2g, 3.6 mmol, 55% yield) as a colorless liquid. MS(ESI) m/z: 267.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=8.02-8.00 (m, 1H) 7.70-7.69 (m, 1H)7.43-7.41 (m, 2H) 3.83-3.73 (m, 6H).

Intermediate 20: Ethyl (2-bromophenyl)(methyl)phosphinate

To a stirred solution of 1-bromo-2-iodobenzene (1.0 g, 3.5 mmol) in DMF(5 mL), were added diethyl methylphosphonite (0.58 g, 4.2 mmol), andK₃PO₄ (2.3 g, 11 mmol). The reaction mixture was purged with nitrogenfor 5 min and charged with Xantphos (0.21 g, 0.35 mmol) and palladium(II) acetate (0.040 g, 0.18 mmol). The reaction mixture was again purgedwith nitrogen for 3 min and heated at 110° C. for 16 h. The reactionmixture was cooled, filtered through Celite pad and the filtrate wasconcentrated under reduced pressure. The crude product was purified byflash chromatography (pet. ether-EtOAc) to yield the Intermediate 20(0.35 g, 1.3 mmol, 38% yield) as a brown liquid. MS(ESI) m/z: 263.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=8.18-8.13 (m, 1H) 7.67-7.65 (m, 1H)7.64-7.38 (m, 2H) 4.07-4.03 (m, 1H) 3.85-3.80 (m, 1H) 1.86 (d, J=15.0Hz, 3H), 1.32 (t, J=7.2 Hz, 3H).

Intermediate 21: 4-Bromo-3-cyclopropyl-2-fluoroaniline

To an ice cooled solution of 3-cyclopropyl-2-fluoroaniline (0.85 g, 5.6mmol) in DMF (11 mL) under argon atmosphere at rt, was added NBS (1.0 g,5.6 mmol). The reaction mixture was gradually warmed to rt over 3 h andquenched with aqueous Na₂S₂O₃ (10 mL). The biphasic mixture wasextracted with EtOAc (30 mL×2). The combined organic layer was washedwith brine (15 mL×2), dried over Na₂SO₄, concentrated under reducedpressure and purified through flash column chromatography (25%EtOAc-Pet.ether) to yield Intermediate 21 (1.2 g, 5.0 mmol, 89% yield)as an orange liquid. ¹H NMR (400 MHz, CDCl₃) δ=7.11 (d, J=8.5 Hz, 1H),6.51 (t, J=8.8 Hz, 1H), 3.67 (br s, 2H), 1.80 (tt, J=8.6, 5.7 Hz, 1H),1.07-0.82 (m, 4H).

Intermediate 22: tert-Butyl(1-(4-bromo-3-cyclopropyl-2-fluorophenyl)-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of Intermediate 21 (1.1 g, 4.8 mmol) in Acn (10mL) at 0° C. under nitrogen was added K₃PO₄ (1.0 g, 4.8 mmol). Theresulting mixture was treated with 2,4-dibromobutanoyl chloride (0.60mL, 4.5 mmol) and stirred for 2 h. Then, K₂CO₃ (2.0 g, 14 mmol) wasadded, and the mixture was stirred for 16 h. The solid was filteredthrough a Celite pad and the pad was washed with Acn (15 mL×2). Thefiltrate was partially evaporated, ammonia (aq, 10 mL, 460 mmol) wasadded, and the mixture was stirred at 40° C. for 16 h. The mixture wasextracted with EtOAc (20 mL×3) and washed with brine (20 mL). Thecombined organics were dried over Na₂SO₄ and evaporated to give crude3-amino-1-(4-bromo-3-cyclopropyl-2-fluorophenyl)pyrrolidin-2-one (1.0 g,3.2 mmol, 67% yield), which was used in next step without furtherpurification.

To a stirred solution of3-amino-1-(4-bromo-3-cyclopropyl-2-fluorophenyl)pyrrolidin-2-one in DCM(15 mL) under argon atmosphere at rt, were added TEA (0.98 mL, 7.0 mmol)and (Boc)₂O (0.90 mL, 3.9 mmol). The reaction mixture was stirred at rtfor 6 hours. Then, the reaction mixture was quenched with aqueoussaturated NH₄Cl (20 mL) and extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,concentrated under reduced pressure and purified via flashchromatography (20% EtOAc-pet. ether) to give Intermediate 22 (1.0 g,2.4 mmol, 69% yield) as a yellowish gummy solid. MS(ESI) m/z: 413.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=7.38 (dd, J=8.5, 1.5 Hz, 1H),7.14-7.09 (m, 1H), 5.18 (br. s., 1H), 4.37-4.33 (m, 1H), 3.86-3.74 (m,1H), 3.69-3.62 (m, 1H), 2.79-2.75 (m, 1H), 2.15-2.01 (m, 1H), 1.80 (tt,J=8.6, 5.7 Hz, 1H), 1.48 (s, 9H), 1.14-1.01 (m, 2H), 0.91-0.84 (m, 2H).

Intermediate 23:tert-Butyl(1-(2-cyclopropyl-2′-(dimethylphosphoryl)-3-fluoro-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

To a solution of Intermediate 22 (0.50 g, 1.2 mmol) in 1,4-dioxane (10mL) at rt, were added (2-bromophenyl)dimethylphosphine oxide (0.42 g,1.8 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.92 g, 3.6 mmol), and K₂CO₃ (0.42 g, 3.0 mmol). The reaction mixturewas purged with nitrogen for 5 min and then charged with PdCl₂(dppf).DCM(0.090 g, 0.12 mmol). The reaction mixture was again purged withnitrogen for 3 min and heated at 100° C. for 16 h. The reaction mixturewas cooled and filtered through a Celite pad, and the filtrate wasconcentrated under reduced pressure. The crude intermediate was purifiedby flash chromatography (MeOH—CHCl₃) to yield Intermediate 23 (0.30 g,0.62 mmol, 51% yield) as an orange solid. MS(ESI) m/z: 487.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ=8.25-8.10 (m, 1H), 7.62-7.48 (m, 2H), 7.33-7.21(m, 2H), 7.07-6.95 (m, 1H), 5.26-5.10 (m, 1H), 4.48-4.27 (m, 1H),3.93-3.79 (m, 1H), 3.79-3.67 (m, 1H), 2.88-2.74 (m, 1H), 2.20-2.01 (m,1H), 1.54-1.37 (m, 16H), 1.04-0.85 (m, 2H), 0.73-0.68 (m, 2H).

Intermediate 24:3-Amino-1-(2-cyclopropyl-2′-(dimethylphosphoryl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrrolidin-2-onehydrochloride

To an ice cooled solution of Intermediate 23(0.33 g, 0.68 mmol) in1,4-dioxane (1 mL) under argon atmosphere at rt, was added 4M HCl in1,4-dioxane (3.0 ml, 12 mmol) and the mixture was stirred at rt for 2 h.The solvent was evaporated under reduced pressure to obtain a gummysolid. The crude product was triturated with pet. ether (10 mL×2) anddried to give Intermediate 24 (0.26 mg, 0.67 mmol, 99% yield) as a browngummy solid. MS(ESI) m/z: 387.1 [M+H]+.

Intermediate 25: tert-Butyl(1-(4-bromo-3-fluoro-2-(trifluoromethyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of 4-bromo-2-fluoro-3-(trifluoromethyl)aniline(0.70 g, 2.7 mmol) in Acn (10 mL) at 0° C. under nitrogen was addedK₃PO₄ (0.58 g, 2.7 mmol). The resulting mixture was treated with2,4-dibromobutanoyl chloride (0.29 mL, 2.2 mmol) and stirred for 2 h.Then, K₂CO₃ (1.1 g, 8.1 mmol) was added, and the reaction mixture wasstirred for 16 h. The mixture was filtered through a Celite pad, and thepad was washed with Acn (15 mL×2). The filtrate was partially evaporatedand ammonia (aq) (10 mL, 462 mmol) was added. The mixture was stirred at40° C. for 16 h and then extracted with EtOAc (20 mL×3). The combinedorganics were washed with brine (20 mL), dried over Na₂SO₄ andevaporated to give crude3-amino-1-(4-bromo-2-fluoro-3-(trifluoromethyl)phenyl)pyrrolidin-2-one(0.88 g, 2.6 mmol, 95% yield), which was used in the next step withoutany further purification.

To a stirred solution of crude3-amino-1-(4-bromo-3-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-2-onein DCM (15 mL) under argon atmosphere at rt, were added TEA (3.7 mL, 26mmol) and (Boc)₂O (3.4 mL, 15 mmol). The reaction mixture was stirred atrt for 6 hours and then quenched with aqueous saturated NH₄Cl (20 mL)and extracted with EtOAc (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, concentrated under reducedpressure and purified via column chromatography (30% EtOAc-pet. ether)to yield Intermediate 25 (4.8 g, 11 mmol, 82% yield) as a yellowishgummy solid. MS(ESI) m/z: 442.8 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ=7.82(t, J=7.8 Hz, 1H), 7.02 (br. d., J=8.7 Hz, 1H), 5.23-5.05 (m, 1H),4.43-4.23 (m, 1H), 3.80-3.53 (m, 2H), 2.89-2.68 (m, 1H), 2.21-2.03 (m,1H), 1.47 (s, 9H).

Intermediate 26: tert-Butyl(1-(2′-(dimethylphosphoryl)-2-fluoro-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

To a solution of Intermediate 25 (0.60 g, 1.4 mmol) in 1,4-dioxane (10mL) at rt, were added (2-bromophenyl)dimethylphosphine oxide (0.41 mg,1.8 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.52 g, 2.0 mmol), and, K₂CO₃ (0.56 mg, 4.1 mmol). The reaction mixturewas purged with nitrogen for 5 min and then 20 charged withPdCl₂(dppf).DCM (56 mg, 0.070 mmol). The reaction mixture was againpurged with nitrogen for 3 min and heated at 100° C. for 16 h. Thereaction mixture was cooled, filtered through a Celite pad and thefiltrate was concentrated under reduced pressure. The crude product waspurified by column chromatography (EtOAc/Pet. Ether) to give theIntermediate 26 (0.30 g, 0.58 mmol, 43% yield) as an orange solid.MS(ESI) m/z: 515.1

Intermediate 27:3-Amino-1-(2′-(dimethylphosphoryl)-2-fluoro-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)pyrrolidin-2-onehydrochloride

To an ice cooled solution of Intermediate 26 (0.30 g, 0.58 mmol) in1,4-dioxane (5 mL) under argon atmosphere at rt, was added 4M HCl in1,4-dioxane (5 mL) and stirred at rt for 2 h. The solvent was evaporatedunder reduced pressure. The solid was triturated with pet. ether (10ml×2) and dried to give the Intermediate 27 (0.20 g, 0.48 mmol, 83%yield) as a brown gummy solid. MS(ESI) m/z: 415.1 [M+H]⁺.

Intermediate 28:(S)-1-(4-Bromo-2,3-difluorophenyl)-5-(hydroxymethyl)pyrrolidin-2-one

To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7 mmol)in 1,4-dioxane (15 mL) at rt, were added 1,4-dibromo-2,3-difluorobenzene(2.4 g, 8.7 mmol), K₃PO₄ (3.7 g, 17 mmol) and,N,N-dimethylethylenediamine (0.15 g, 1.7 mmol). The reaction mixture waspurged with nitrogen for 5 min and then charged with copper (I) iodide(0.17 g, 0.87 mmol). The reaction mixture was again purged with nitrogenfor 3 min and heated at 95° C. for 12 h. The reaction mixture wascooled, filtered through a Celite pad and the filtrate was concentratedunder reduced pressure. The crude compound was purified by columnchromatography (3% MeOH—CHCl₃) to yield Intermediate 28 (0.80 g, 2.6mmol, 30% yield) as a yellowish solid. MS(ESI) m/z: 305.9 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ=7.59 (ddd, J=8.8, 7.0, 2.3 Hz, 1H), 7.24 (ddd,J=9.0, 7.0, 2.0 Hz, 1H), 4.80 (t, J=5.0 Hz, 1H), 4.20-4.04 (m, 1H), 3.37(dd, J=5.0, 4.0 Hz, 2H), 2.56-2.45 (m, 1H), 2.43-2.35 (m, 1H), 2.25-2.18(m, 1H), 2.07-1.95 (m, 1H).

Intermediate 29:(S)-1-(4-Bromo-2,3-difluorophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one

To a stirred solution of Intermediate 28 (0.80 g, 2.6 mmol) in DCM (10mL) under argon atmosphere at rt, were added TEA (0.55 mL, 3.9 mmol) andtert-butyldimethylsilyl chloride (0.43 g, 2.9 mmol). The reactionmixture was stirred at rt for 16 h. The reaction mixture was quenchedwith aqueous saturated NH₄Cl (20 mL) and extracted with DCM (20 mL×2).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, concentrated under reduced pressure. The crude product waspurified via column chromatography (15% EtOAc-Pet. ether) to giveIntermediate 29 (0.85 g, 2.0 mmol, 77% yield) as a white solid. MS(ESI)m/z: 420.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=7.35 (m, 1H), 7.15-7.05 (m,1H), 4.24-4.17 (m, 1H), 3.62-3.49 (m, 2H), 2.69-2.63 (m, 1H), 2.54-2.50(m, 1H), 2.41-2.26 (m, 1H), 2.14-2.03 (m, 1H), 0.84 (s, 9H), −0.02 (s,3H), −0.05 (s, 3H).

Intermediate 30:(3R,5S)-3-azido-1-(4-bromo-2,3-difluorophenyl-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one

To a stirred solution of Intermediate 29 (1.0 g, 2.4 mmol) in THF (20mL) at −78° C., lithium diisopropylamide (1.8 mL, 3.6 mmol) was addedand stirring was continued for 30 min. Then, a solution of2,4,6-triisopropylbenzenesulfonyl azide (1.0 g, 3.3 mmol) in THF (5 mL)was cannulated into the mixture and the mixture was stirred for 4 h.Then, the reaction mixture was quenched with saturated aqueous NaHCO₃ (2mL) and gradually warmed to rt. The reaction mixture was diluted withEtOAc (40 mL), washed with H₂O (10 mL×2) and brine (20 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (15% EtOAc-Pet ether, 40 g column) toyield Intermediate 30 (0.85 g, 1.8 mmol, 77% yield) as an orange solid.MS(ESI) m/z: 461.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=7.65 (ddd, J=9.0,7.0, 2.0 Hz, 1H), 7.36-7.28 (m, 1H), 4.72-4.64 (m, 1H), 4.33-4.24 (m,1H), 3.63-3.52 (m, 2H), 2.48-2.28 (m, 1H), 2.14 (dt, J=13.3, 8.7 Hz,1H), 0.91-0.66 (m, 9H), −0.06 (s, 3H), −0.08 (s, 3H).

Intermediate 31: tert-Butyl((3R,5S)-1-(4-bromo-2,3-difluorophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution Intermediate 30 (0.85 g, 1.8 mmol) in THF (8 mL)were added triphenylphosphine (0.73 g, 2.8 mmol) and H₂O (0.8 mL). Thereaction mixture was stirred at rt for 3 h and heated at 65° C. for 6 h.The solvent was evaporated under reduced pressure and used for the nextstep without further purification. To a stirred solution of crude(5S)-3-amino-1-(4-bromo-2,3-difluorophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-onein DCM (5 mL) under argon atmosphere at rt, were added Boc-anhydride(0.84 mL, 3.6 mmol) and TEA (0.75 mL, 5.4 mmol. The reaction mixture wasstirred at rt for 2 h. Then, the reaction mixture was quenched withaqueous saturated NH₄Cl (15 mL) and extracted with CHCl₃ (20 mL×2). Thecombined organic layers were washed with brine (15 mL), dried overNa₂SO₄, concentrated under reduced pressure. The crude product waspurified via column chromatography (15% EtOAc-Pet. ether) to giveIntermediate 31 (0.80 g, 1.5 mmol, 83% yield) as a white solid. MS(ESI)m/z: 535.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=7.41-7.32 (m, 1H),7.15-7.01 (m, 1H), 5.02-5.22 (m, 1H), 4.73-4.61 (m, 1H), 4.52-4.43 (m,1H), 4.21-4.10 (m, 1H), 3.61-3.52 (m, 1H), 2.63-2.51 (m, 1H), 2.35-2.31(m, 1H), 1.43 (s, 9H), 0.84 (s, 9H), −0.06 (s, 3H), −0.08 (s, 3H).

Intermediate 32: tert-Butyl((3R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of Intermediate 31 (0.80 g, 1.49 mmol) in1,4-dioxane (10 mL), were added (2-bromophenyl)dimethylphosphine oxide(0.52 g, 2.2 mmol), bis(pinacolato)diboron (1.1 g, 4.5 mmol), and K₂CO₃(0.42 mg, 3.0 mmol). The reaction mixture was purged with argon for 5min and charged with PdCl₂(dppf)-CH₂Cl₂ adduct (0.13 mg, 0.15 mmol). Thereaction mixture was again purged with nitrogen for 3 min and heated at100° C. for 12 h. The reaction mixture was cooled, filtered through aCelite pad and the filtrate was concentrated under reduced pressure. Thecrude product was purified by column chromatography (MeOH/CHCl₃) toyield Intermediate 32 (0.40 g, 0.66 mmol, 44% yield) as a brown solid.MS(ESI) m/z: 609.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ=8.01-7.97 (m,1H), 7.85-7.81 (m, 1H), 7.80-7.64 (m, 2H), 7.59-7.27 (m, 3H), 4.66-4.56(m, 1H), 4.42-4.33 (m, 1H), 3.76-3.55 (m, 2H), 2.46-2.28 (m, 2H),1.54-1.39 (m, 15H), 0.84 (s, 9H), 0.06 (s, 3H), −0.08 (s, 3H).

Intermediate 33:(3R,5S)-3-amino-1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-5-(hydroxymethyl)pyrrolidin-2-onehydrochloride

To an ice cooled solution of Intermediate 32 (0.40 g, 0.66 mmol) in1,4-dioxane (1 mL) under argon atmosphere at rt, was added 4M HCl in1,4-dioxane (2.5 mL, 10 mmol) and stirred at rt for two h. The solventwas evaporated under reduced pressure and the gummy solid was furthertriturated with EtOAc (10 ml×2) and dried to give Intermediate 33 (0.22g, 0.56 mmol, 85% yield) as a brown solid. MS(ESI) m/z: 395.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ=7.97-7.88 (m, 1H), 7.82-7.72 (m, 1H), 7.69-7.47(m, 2H), 7.43-7.25 (m, 2H), 4.35-4.29 (m, 2H), 4.11-3.86 (m, 4H),3.55-3.34 (m, 2H), 2.48-2.27 (m, 2H), 1.52 (br d, J=13.1 Hz, 6H).

Intermediate 34: 1-(4-Bromo-2,3-difluorophenyl)-5-methylpyrrolidin-2-one

To a solution of racemic 5-methylpyrrolidin-2-one (1.0 g, 10 mmol) in1,4-dioxane (10 mL) at rt, were added 1,4-dibromo-2,3-difluorobenzene(3.3 g, 12 mmol), K₃PO₄ (4.3 g, 20 mmol) andN,N′-dimethylethylenediamine (0.18 g, 2.0 mmol). The reaction mixturewas purged with nitrogen for 5 min and then charged with copper (I)iodide (0.19 g, 1.0 mmol). The reaction mixture was again purged withnitrogen for 3 min and heated at 80° C. for 6 h. The reaction mixturewas cooled, filtered through a Celite pad and the filtrate wasconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (pet. ether-EtOAc) to give Intermediate 34 (0.90g, 3.1 mmol, 31% yield) as brown liquid. MS(ESI) m/z: 291.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ=7.38-7.01 (m, 1H), 6.99-6.96 (m, 1H), 4.24-4.20(m, 1H), 2.62-2.51 (m, 2H), 2.50-2.38 (m, 1H), 1.81-1.76 (m, 1H), 1.17(d, J=6.4 Hz, 3H).

Intermediate 35:3-Azido-1-(4-bromo-2,3-difluorophenyl)-5-methylpyrrolidin-2-one

To a stirred solution of Intermediate 34 (0.20 g, 0.69 mmol) in THF (3mL) at −78° C., lithium diisopropylamide (0.69 mL, 1.4 mmol) was addedand stirring was continued for 40 min. Then, a solution of2,4,6-triisopropylbenzenesulfonyl azide (0.26 g, 0.83 mmol) in THF (2mL) was cannulated into the mixture and the mixture was stirred for 4 h.The mixture was then quenched with saturated aqueous NH₄Cl (10 mL),gradually warmed to rt and extracted with EtOAc (20 mL×2). The combinedorganic layers were washed with brine (15 mL), dried over Na₂SO₄, andconcentrated under reduced pressure.

The crude residue was purified by column chromatography (12% EtOAc-Petether) to yield Intermediate 35 (0.10 g, 0.21 mmol, 31% yield) as anorange solid. MS(ESI) m/z: 331.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃)δ=7.40-7.36 (m, 1H), 7.04-6.98 (m, 1H), 4.36-4.31 (m, 1H), 4.26-4.21 (m,1H), 2.32-2.26 (m, 1H), 2.14-2.043 (m, 1H), 1.16 (d, J=6.4 Hz, 3H).

Intermediate 36: tert-Butyl(1-(4-bromo-2,3-difluorophenyl)-5-methyl-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution3-azido-1-(4-bromo-2,3-difluorophenyl)-5-methylpyrrolidin-2-one (1.5 g,4.5 mmol) in THF (21 mL) were added triphenylphosphine (2.4 g, 9.1 mmol)and water (3 mL). The reaction mixture was stirred at rt for 30 min andheated to 65° C. for 6 h. The solvent was evaporated under reducedpressure and the crude product used for the next step without furtherpurification.

To a stirred solution of crude3-amino-1-(4-bromo-2,3-difluorophenyl)-5-methylpyrrolidin-2-one in DCM(20 mL) under argon atmosphere at rt, were added TEA (0.82 mL, 5.9 mmol)and Boc-anhydride (1.4 mL, 5.9 mmol). The reaction mixture was stirredat rt for 2 h. Then, the reaction mixture was quenched with aqueoussaturated NH₄Cl (25 mL) and extracted with CHCl₃ (30 mL×2). The combinedorganic layers were washed with brine (25 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The crude product was purified viacolumn chromatography (50% EtOAc-Pet. ether) to give Intermediate 36(1.3 g, 3.2 mmol, 82% yield) as a brown solid. MS(ESI) m/z: 405.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=7.39-7.26 (m, 1H), 7.0-6.99 (m, 1 H),5.29-5.07 (m, 1H), 4.58-4.31 (m, 1H), 4.30-4.13 (m, 1H), 2.51-2.04 (m,1H), 1.81-1.76 (m, 1H), 1.45 (s, 9H), 1.30-1.15 (m, 3H). (Mixture ofdiastereomers)

Intermediate 37: tert-Butyl(1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-5-methyl-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of Intermediate 36 (1.0 g, 2.5 mmol) in1,4-dioxane (15 mL), were added (2-bromophenyl)dimethylphosphine oxide(0.58 g, 2.5 mmol), bis(pinacolato)diboron (1.9 g, 7.4 mmol) and K₂CO₃(1.0 g, 7.4 mmol). The reaction mixture was purged with nitrogen for 5min and charged with PdCl₂(dppf).CH₂Cl₂ adduct (0.20 g, 0.25 mmol). Thereaction mixture was again purged with nitrogen for 3 min and heated at110° C. for 15 h. The mixture was cooled, filtered through a Celite padand the filtrate was concentrated under reduced pressure. The crudecompound was purified by flash chromatography (MeOH/CDCl₃) to giveIntermediate 37 (0.70 g, 1.5 mmol, 59% yield) as a brown solid. MS(ESI)m/z: 479.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=7.78-7.73 (m, 1H),7.62-7.51 (m, 3H), 7.37-7.28 (m, 1H), 7.23-7.18 (m, 1H), 5.31-5.11 (m,1H), 4.59-4.24 (m, 2H), 2.58-2.32 (m, 1H), 1.77-1.74 (m, 3H), 1.65-1.49(m, 13H), 1.30-1.23 (m, 3H). (Mixture of diastereomers)

Intermediate 38:3-Amino-1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-5-methylpyrrolidin-2-onehydrochloride

To an ice cooled solution of Intermediate 37 (0.70 g, 1.5 mmol) in1,4-dioxane (5 mL) under argon atmosphere, was added 4M HCl (7.3 mL, 29mmol) in 1,4-dioxane and stirred at rt for 2 h. The solvent wasevaporated under reduced pressure to give Intermediate 38 (0.50 g, 1.2mmol, 82% yield) as brown liquid. MS(ESI) m/z: 379.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ=7.78-7.73 (m, 1H), 7.62-7.51 (m, 3H), 7.37-7.28 (m, 1H),7.23-7.18 (m, 1H), 5.38-4.98 (m, 3H), 4.59-4.42 (m, 2H), 2.58-2.29 (m,1H), 1.71-1.63 (m, 3H), 1.55-1.49 (m, 4H), 1.30-1.23 (m, 3H).

Example 1:(R)—N-(4′-(3-(3-(4-Chlorophenyl)ureido)-2-oxopyrrolidin-1-yl)-2′,3′-difluoro-[1,1′-biphenyl]-2-yl)methanesulfonamide

To a stirred solution of Intermediate 5 (50 mg, 0.12 mmol), in DCE (2mL) under nitrogen at rt, DIPEA (0.084 mL, 0.48 mmol), and1-chloro-4-isocyanatobenzene (22.0 mg, 0.144 mmol) were addedsequentially. The resulting reaction mixture was stirred at rt for 4 h.The reaction mixture was quenched with water and extracted with EtOAc.The organic layer was washed with ice cold water, brine, dried overNa₂SO₄, and concentrated under reduced pressure. The crude compound waspurified by reverse phase chromatography followed by chiral HPLC toExample 1 (16 mg, 0.028 mmol, 24%). RT=1.732 min, 94.2%, (Method C);MS(ESI) m/z: 535.1 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆): δ 9.17 (s, 1H),8.87 (s, 1H), 7.96 (s, 1H), 7.58-7.29 (m, 10H), 4.64-4.48 (m, 1H),3.96-3.82 (m, 1H), 3.81-3.66 (m, 1H), 2.74 (s, 3H), 2.59-2.55 (m, 1H),2.20-2.07 (m, 1H).

Example 25:(R)-1-(4-chloro-2-fluorophenyl)-3-(1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)urea

DIEA (61 mL, 350 mmol) was added to a solution of Intermediate 10 (28 g,70 mmol) in DCE (560 mL) slowly at 0° C. After stirring for 2 min,Intermediate 11 (17 g, 63 mmol) was added, and the reaction mixture wasslowly heated to 50° C. and stirred for 12 h. The reaction mixture wasconcentrated under reduced pressure, and the crude product was purifiedvia column chromatography (5% MeOH in DCM). The product was purified byprep HPLC, washed with water, and dried to obtain Example 25 (29 g, 54mmol, 78% yield) as a white solid.

Example 57:(R)-1-(1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

DIEA (5.5 mL, 6.2 mmol) was added to a solution of Intermediate 10 (2.5g, 6.2 mmol) in DCE (70 mL) slowly at 0° C. After stirring for 2 min,Intermediate 12 (1.7 g, 5.6 mmol) was added, and the reaction mixturewas slowly heated to 50° C. and stirred for 8 h. The reaction mixturewas concentrated under reduced pressure and the crude product waspurified via column chromatography (6.5% MeOH in DCM). The product waspurified by prep HPLC, washed with water, and dried to obtain Example 57(2.2 g, 3.9 mmol, 62% yield) as a white solid.

Example 73:(R)-1-(1-(4-(2-(dimethylphosphoryl)pyridin-3-yl)-2,3-difluorophenyl)-2-oxopyrrolidin-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

To a solution of Intermediate 14 (13 g, 24 mmol) and Intermediate 15(5.6 g, 24 mmol) in 1,4 dioxane (260 mL) and water (26 mL), were addedpotassium phosphate (10 g, 48 mmol) and PdCl₂(dppf)-CH₂Cl₂ (2.0 g, 2.4mmol). The reaction mixture was stirred for 30 min, slowly raised to110° C. and stirred for 12 h. The mixture was filtered through Celite,and the plug was washed with EtOAc. The filtrate was dried over sodiumsulfate and concentrated under reduced pressure. The crude compound waspurified via column chromatography (2% MeOH in DCM) to yield Example 73(9.1 g, 16 mmol, 66% yield).

Example 89:(R)-1-(1-(2-Cyclopropyl-2′-(dimethylphosphoryl)-3-fluoro-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

To an ice cooled suspension of Intermediate 24 (0.13 g, 0.34 mmol) inDMF (2 mL) under argon atmosphere at rt, were added DIEA (0.18 mL, 1.0mmol) and Intermediate 12 (0.12 g, 0.41 mmol). Then, the resultingsolution was heated at 50° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure and the crude product was purifiedby reverse phase chromatography followed by chiral HPLC to give Example89 (0.07 g, 0.12 mmol, 33% yield).

Example 91:(R)-1-(4-Chloro-2-fluorophenyl)-3-(1-(2′-(dimethylphosphoryl)-2-fluoro-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)urea

To an ice cooled suspension of Intermediate 27 (0.080 g, 0.18 mmol) inDCE (2 mL) under argon atmosphere at rt, were added DIEA (0.06 mL, 0.36mmol) and Intermediate 11 (0.060 g, 0.21 mmol). Then, the resultingsolution was heated at 50° C. for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the crude product was purifiedby reverse phase chromatography followed by chiral HPLC to yield Example91 (0.060 g, 0.11 mmol, 60% yield) as a white solid.

Example 109:1-(4-Chloro-2-fluorophenyl)-3-(1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-5-methyl-2-oxopyrrolidin-3-yl)urea

To an ice cooled suspension of Intermediate 38 (0.20 g, 0.48 mmol) inDCE (10 mL) under argon atmosphere at rt, were added DIEA (0.34 mL, 1.9mmol) and Intermediate 11 (73 mg, 0.25 mmol). Then, the resultingsolution was heated at 50° C. for 3 h. The reaction mixture wasconcentrated under reduced pressure and the crude product was purifiedby reverse phase chromatography followed by chiral HPLC to yield Example109 (0.02 g, 0.04 mmol, 8.3% yield) as a white solid.

Example 112:1-(4-Chloro-2-fluorophenyl)-3-((3R,5S)-1-(2′-(dimethylphosphoryl)-2,3-difluoro-[1,1′-biphenyl]-4-yl)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl)urea

To an ice cooled suspension of Intermediate 22 (0.11 g, 0.28 mmol) inDMF (2 mL) under argon atmosphere at rt, were added DIEA (0.15 mL, 0.84mmol) and Intermediate 11 (0.11 g, 0.42 mmol). Then, the resultingsolution was heated at 50° C. for 3 h. The reaction mixture wasconcentrated under reduced pressure and the crude product was purifiedby reverse phase chromatography followed by chiral HPLC to yield Example112 (0.05 g, 0.08 mmol, 29% yield).

The following Examples in Table 1 were made by using the same procedureas shown above in Examples 1, 25, 57, 73, 89, 91, 109, and 112.

HPLC Method, RT LCMS (min.) & Ex Structure (M + H)+ Purity ¹H NMR 2

490.1 Method D, RT = 1.75 min, 99.3% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(d, J = 2.2 Hz, 1H), 8.16 (t, J = 8.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H),7.54-7.32 (m, 4H), 7.31-7.08 (m, 4H), 5.16 (t, J = 5.5 Hz, 1H),4.63-4.48 (m, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.97-3.85 (m, 1H), 3.84-3.74 (m, 1H), 2.65-2.56 (m, 1H), 2.16- 2.03 (m, 1H). 3

472.1 Method D, RT = 1.89 min, 98.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.86(s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.54- 7.34 (m, 5H), 7.34-7.14 (m,4H), 6.72 (d, J = 7.3 Hz, 1H), 5.16 (t, J = 5.4 Hz, 1H), 4.55 (dt, J =10.1, 8.1 Hz, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.95-3.83 (m, 1H), 3.83-3.72 (m, 1H), 2.60-2.54 (m, 1H), 2.19- 2.06 (m, 1H). 4

588.2 (M + NH₄)⁺ Method D, RT = 1.66 min, 95.2% ¹H NMR (400 MHz,DMSO-d₆) δ = 9.18 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.60- 7.45 (m,2H), 7.45-7.31 (m, 4H), 7.26- 7.20 (m, 1H), 7.03-6.97 (m, 1H), 4.60-4.52 (m, 1H), 3.98-3.82 (m, 2H), 3.79- 3.73 (m, 1H), 2.87 (s, 3H),2.18-2.06 (m, 1H). 5

553.1 Method C, RT = 1.79 min, 96.8% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.18(s, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.56-7.29(m, 6H), 7.29- 7.13 (m, 3H), 4.64-4.48 (m, 1H), 3.96- 3.87 (m, 1H),3.78-3.74 (m, 1H), 2.74 (s, 3H), 2.62-2.56 (m, 1H), 2.13-2.01 (m, 1H). 6

569.1 Method C, RT = 1.86 min, 97.2% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.16(s, 1H), 7.96 (s, 1H), 7.70-7.56 (m, 4H), 7.55-7.45 (m, 2H), 7.44-7.30(m, 3H), 7.28-7.20 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 4.60-4.54 (m, 1H),3.96-3.86 (m, 1H), 3.77-3.75 (m, 1H), 2.74 (s, 3H), 2.61- 2.54 (m, 1H),2.21-2.06 (m, 1H). 7

538.2 Method D, RT = 1.75 min, 95.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(s, 1H), 8.23-8.05 (m, 2H), 7.91-7.68 (m, 2H), 7.51 (d, J = 7.3 Hz, 1H),7.46- 7.35 (m, 2H), 7.35-7.25 (m, 1H), 7.20- 7.18 (m, 2H), 4.63-4.48 (m,1H), 3.94- 3.87 (m, 1H), 3.83-3.69 (m, 1H), 3.05 (s, 3H), 2.63-2.54 (m,1H), 2.10-2.05 (m, 1H). 8

467.2 Method D, RT = 1.85 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.88(s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.96- 7.85 (m, 1H), 7.79-7.63 (m,2H), 7.59- 7.49 (m, 1H), 7.49-7.37 (m, 3H), 7.30 (d, J = 8.8 Hz, 2H),6.75 (d, J = 7.6 Hz, 1H), 4.63-4.51 (m, 1H), 3.98-3.87 (m, 1H),3.87-3.73 (m, 1H), 2.58 (br. s., 1H), 2.18-2.11 (m, 1H). 9

485.1 Method D, RT = 1.91 min, 96.8% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(s, 1H), 8.15 (t, J = 8.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.94-7.83(m, 1H), 7.78- 7.60 (m, 2H), 7.57-7.49 (m, 1H), 7.48- 7.34 (m, 2H), 7.20(d, J = 7.6 Hz, 2H), 4.64- 4.52 (m, 1H), 3.98-3.88 (m, 1H), 3.86- 3.76(m, 1H), 2.65-2.55 (m, 1H), 2.18- 2.00 (m, 1H). 10

520.1 Method D, RT = 1.69 min, 99.1% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.88(s, 1H), 8.15 (dd, J = 7.7, 1.3 Hz, 1H), 7.89-7.71 (m, 2H), 7.52 (dd, J= 7.3, 1.5 Hz, 1H), 7.49-7.37 (m, 3H), 7.36-7.22 (m, 3H), 6.74 (d, J =7.6 Hz, 1H), 4.62- 4.49 (m, 1H), 3.97-3.85 (m, 1H), 3.84- 3.73 (m, 1H),3.06 (s, 3H), 2.60-2.54 (m, 1H), 2.19-2.07 (m, 1H). 11

554.2 Method D, RT = 1.81 min, 97.1% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.18(s, 1H), 8.15 (dd, J = 7.8, 1.5 Hz, 1H), 7.90-7.72 (m, 2H), 7.70-7.55(m, 4H), 7.52 (dd, J = 7.5, 1.3 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H),7.36-7.25 (m, 1H), 6.86 (d, J = 7.3 Hz, 1H), 4.65-4.50 (m, 1H),4.00-3.86 (m, 1H), 3.81-3.77 (m, 1H), 3.06 (s, 3H), 2.62-2.54 (m, 1H),2.16- 2.11 (m, 1H). 12

485.2 Method D, RT = 1.50 min, 96.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.94(s, 1H), 7.62 (s, 1H), 7.49-7.34 (m, 7H), 7.31-7.23 (m, 2H), 6.81 (d, J= 7.3 Hz, 1H), 4.61-4.50 (m, 1H), 4.16 (q, J = 6.8 Hz, 1H), 3.92-3.84(m, 1H), 3.79-3.74 (m, 1H), 3.60-3.20 (m, 2H), 2.61-2.54 (m, 1H),2.17-2.07 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H). 13

554.1 Method D, RT = 1.67 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.40(s, 1H), 9.15 (s, 1H), 8.77 (d, J = 7.1 Hz, 1H), 8.17 (d, J = 2.2 Hz,1H), 7.98 (dd, J = 10.3, 2.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.41-7.27 (m,3H), 7.20 (t, J = 7.1 Hz, 1H), 4.68-4.55 (m, 1H), 3.95-3.81 (m, 2H),2.86 (s, 3H), 2.60-2.55 (m, 1H), 2.28-2.14 (m, 1H). 14

533.2 Method C, RT = 2.07 min, 99.2% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.19(s, 1H), 8.96 (br. s., 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.65-7.56 (m, 4H),7.45 (d, J = 8.8 Hz, 2H), 7.41-7.27 (m, 4H), 6.81 (d, J = 7.6 Hz, 1H),4.58-4.49 (m, 1H), 3.89-3.79 (m, 2H), 2.73 (s, 3H), 2.51-2.50 (m, 1H),2.10-2.01 (m, 1H). 15

537.2 Method D, RT = 1.54 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.71(s, 1H), 9.13 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 7.55 (d, J = 7.6 Hz,1H), 7.51- 7.45 (m, 2H), 7.41-7.31 (m, 3H), 7.24- 7.17 (m, 1H),4.58-4.49 (m, 1H), 3.89- 3.79 (m, 2H), 2.88 (s, 3H), 2.51-2.50 (m, 1H),2.20-2.10 (m, 1H). 16

460.1 Method D, RT = 2.00 min, 92.1% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.88(s, 1H), 7.62-7.50 (m, 2H), 7.50-7.42 (m, 3H), 7.42-7.33 (m, 3H),7.33-7.22 (m, 2H), 6.75 (d, J = 7.3 Hz, 1H), 4.65- 4.49 (m, 1H),3.97-3.84 (m, 1H), 3.84- 3.70 (m, 1H), 2.61-2.53 (m, 1H), 2.21- 2.04 (m,1H). 17

536.1 Method D, RT = 1.66 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.43(s, 1H), 9.15 (br. s., 1H), 8.23 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 7.8Hz, 1H), 7.80 (dd, J = 8.8, 2.7 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H),7.50-7.44 (m, 2H), 7.40-7.27 (m, 3H), 7.20 (t, J = 7.1 Hz, 1H),4.63-4.54 (m, 1H), 3.95-3.81 (m, 2H), 2.86 (s, 3H), 2.60-2.55 (m, 1H),2.21-2.11 (m, 1H). 18

571.2 Method D, RT = 1.68 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 10.13(s, 1H), 9.12 (br. s., 1H), 9.05 (s, 1H), 8.73 (s, 1H), 7.89 (d, J = 7.6Hz, 1H), 7.52- 7.46 (m, 2H), 7.41-7.31 (m, 3H), 7.25- 7.16 (m, 1H),4.66-4.60 (m, 1H), 3.95- 3.81 (m, 2H), 2.60-2.55 (m, 1H), 2.88 (s, 3H),2.24-2.13 (m, 1H). 19

461.1 Method D, RT = 1.73 min, 96.8% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.88(s, 1H), 8.38 (d, J = 4.6 Hz, 1H), 8.16 (t, J = 7.9 Hz, 1H), 7.56 (t, J= 6.2 Hz, 1H), 7.53-7.35 (m, 4H), 7.30 (d, J = 9.0 Hz, 2H), 6.74 (d, J =7.3 Hz, 1H), 4.64-4.49 (m, 1H), 3.96-3.85 (m, 1H), 3.84-3.73 (m, 1H),2.61-2.54 (m, 1H), 2.21-2.01 (m, 1H). 20

534.2 Method D, RT = 1.63 min, 98.8% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.43(s, 1H), 8.95 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.19 (dd, J = 8.7, 1.8Hz, 1H), 7.88- 7.71 (m, 3H), 7.52 (d, J = 8.8 Hz, 2H), 7.47-7.28 (m,4H), 6.99 (d, J = 7.3 Hz, 1H), 4.64-4.54 (m, 1H), 3.99-3.78 (m, 2H),2.74 (s, 3H), 2.50-2.46 (m, 1H) 2.15-2.02 (m, 1H). 21

478.1 Method D, RT = 2.05 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(d, J = 2.2 Hz, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.61-7.50 (m, 2H),7.50-7.32 (m, 5H), 7.27-7.14 (m, 2H), 4.64-4.50 (m, 1H), 3.98-3.85 (m,1H), 3.84-3.75 (m, 1H), 2.64-2.55 (m, 1H), 2.17-2.01 (m, 1H). 22

485.2 Method D, RT = 1.55 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.97(s, 1H), 7.61 (s, 1H), 7.53-7.33 (m, 7H), 7.33-7.22 (m, 2H), 6.84 (d, J= 7.3 Hz, 1H), 4.55 (m, 1H), 4.14 (q, J = 6.8 Hz, 1H), 3.91-3.84 (m,1H), 3.78-3.73 (m, 1H), 2.64-2.55 (m, 1H), 2.12 (m, 1H), 1.34 (d, J =6.6 Hz, 3H). 23

554.2 Method D, RT = 1.46 min, 94.8% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.83(br. s, 1H), 8.63 (br. s., 1H), 8.16 (t, J = 8.9 Hz, 1H), 8.08 (br. s.,1H), 7.47-7.32 (m, 2H), 7.32-7.10 (m, 4H), 6.65 (br. s., 1H), 4.64-4.48(m, 1H), 3.92-3.82 (m, 1H), 3.75 (t, J = 8.7 Hz, 1H), 2.95 (br. s., 3H),2.63-2.54 (m, 1H), 2.21-1.96 (m, 1H). 24

521.1 Method D, RT = 1.62 min, 99.7% 1H NMR (400 MHz, DMSO-d₆) δ 9.47(s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.01-7.89(m, 1H), 7.88- 7.72 (m, 3H), 7.65 (d, J = 9.3 Hz, 1H), 7.55-7.46 (m,1H), 7.43 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.0 Hz, 1H), 4.67-4.56 (m,1H), 3.97-3.87 (m, 1H), 3.85-3.77 (m, 1H), 3.06 (s, 3H), 2.63-2.55 (m,1H), 2.20-2.10 (m, 1H). 25

536.2 Method D, RT = 1.476 min, 98.6% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(br. s, 1H), 8.16 (t, J = 9.0 Hz, 1H), 7.97- 7.84 (m, 1H), 7.69-7.57 (m,2H), 7.43 (dd, J = 11.0, 2.5 Hz, 1H), 7.40-7.32 (m, 2H), 7.32-7.23 (m,1H), 7.23-7.12 (m, 2H), 4.56 (dt, J = 9.9, 8.1 Hz, 1H), 3.95- 3.85 (m,1H), 3.78 (br. t., J = 8.8 Hz, 1H), 2.63-2.54 (m, 1H), 2.14-1.99 (m,1H), 1.52 (br. d., J = 13.1 Hz, 6H). 26

557.2 Method D, RT = 1.89 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.95(br. s., 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.17 (t, J = 8.9 Hz, 1H),7.52-7.24 (m, 7H), 7.23-7.13 (m, 2H), 7.12 (s, 1H), 4.63- 4.47 (m, 1H),3.82 (td, J = 9.5, 6.5 Hz, 1H), 3.71-3.59 (m, 1H), 2.86 (s, 3H),2.63-2.56 (m, 1H), 2.17-2.04 (m, 1H), 2.01-1.95 (m, 1H), 1.04-0.83 (m,2H), 0.80-0.58 (m, 2H). 27

559.2 Method D, RT = 1.868 min, 99.6% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.01(s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.17 (t, J = 8.9 Hz, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.48-7.32 (m, 6H), 7.32-7.26 (m, 1H), 7.25-7.12 (m, 2H),4.60-4.50 (m, 1H), 3.82-3.71 (m, 1H), 3.56 (t, J = 9.3 Hz, 1H),3.06-3.02 (m, 1H) 2.81 (s, 3H), 2.65-2.56 (m, 1H), 2.12-2.02 (m, 1H),1.31-1.13 (m, 6H). 28

464.1 Method D, RT = 1.732 min, 98.6% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.62(d, J = 2.2 Hz, 1H), 8.15 (t, J = 8.9 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H),7.80-7.68 (m, 1H), 7.49-7.28 (m, 2H), 7.24-7.06 (m, 2H), 6.73-6.61 (m,1H), 4.63-4.46 (m, 1H), 3.94 (s, 3H), 3.91-3.78 (m, 1H), 3.78-3.67 (m,1H), 2.64-2.53 (m, 1H), 2.16-2.01 (m, 1H). 29

572.2 Method C, RT = 1.887 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(s, 1H), 8.41 (t, J = 8.4 Hz, 1H), 8.15 (dd, J = 7.9, 1.3 Hz, 1H),7.90-7.72 (m, 2H), 7.66 (dd, J = 11.5, 1.7 Hz, 1H), 7.51 (dd, J = 7.5,1.3 Hz, 2H), 7.46-7.37 (m, 1H), 7.37-7.21 (m, 2H), 4.65-4.51 (m, 1H),4.00-3.87 (m, 1H), 3.81 (t, J = 8.8 Hz, 1H), 3.06 (s, 3H), 2.65-2.56 (m,1H), 2.20-2.02 (m, 1H). 30

580.1 Method C, RT = 1.632 min, 98.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(s, 1H), 8.14 (t, J = 8.8 Hz, 1H), 8.01- 7.87 (m, 1H), 7.72-7.57 (m,2H), 7.48- 7.36 (m, 2H), 7.29 (m, 2H), 7.23-7.16 (m, 1H), 7.10 (d, J =7.6 Hz, 1H), 4.70- 4.58 (m, 1H), 4.39-4.27 (m, 1H), 3.51- 3.43 (m, 1H),3.39-3.35 (m, 1H), 3.24 (s, 3H), 2.46-2.44 (m, 1H), 2.34-2.26 (m, 1H),1.61-1.40 (m, 6H) 31

524.2 Method D, RT = 1.719 min, 99.2% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(d, J = 2.4 Hz, 1H), 8.41 (t, J = 8.2 Hz, 1H), 7.72-7.58 (m, 2H),7.55-7.31 (m, 5H), 7.30-7.17 (m, 2H), 5.16 (t, J = 5.5 Hz, 1H),4.64-4.53 (m, 1H), 4.35 (d, J = 5.6 Hz, 2H), 3.97-3.84 (m, 1H), 3.80 (t,J = 8.7 Hz, 1H), 2.61 (dd, J = 19.4, 6.7 Hz, 1H), 2.15-2.03 (m, 1H). 32

535.2 Method C, RT = 1.550 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.11(br. s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.56(t, J = 8.2 Hz, 1H), 7.50-7.28 (m, 7H), 7.24-7.12 (m, 2H), 4.60-4.50 (m,1H), 3.92-3.82 (m, 1H), 3.74 (t, J = 8.4 Hz, 1H), 2.86 (s, 3H), 2.60(dd, J = 12.0, 8.1 Hz, 1H), 2.14- 2.03 (m, 1H). 33

587.2 Method C, RT = 1.726 min, 98.1% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.12(br. s., 1H), 8.93 (d, J = 2.9 Hz, 1H), 8.41 (t, J = 8.3 Hz, 1H), 7.66(d, J = 11.7 Hz, 1H), 7.56-7.43 (m, 3H), 7.43-7.27 (m, 4H), 7.23 (t, J =7.1 Hz, 1H), 4.66-4.54 (m, 1H), 4.00-3.86 (m, 1H), 3.78 (t, J = 9.2 Hz,1H), 2.91 (s, 3H), 2.66-2.57 (m, 1H), 2.16-2.04 (m, 1H). 34

565.2 Method C, RT = 1.606 min, 96.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.78(s, 1H), 8.63 (d, J = 2.7 Hz, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.53-7.46(m, 1H), 7.46- 7.36 (m, 2H), 7.34-7.15 (m, 5H), 7.11 (dd, J = 8.4, 1.6Hz, 1H), 4.60-4.49 (m, 1H), 3.94-3.80 (m, 1H), 3.74-3.72 (m, 1H), 3.66(s, 3H), 2.90 (s, 3H), 2.63- 2.54 (m, 1H), 2.12-2.01 (m, 1H). 35

502.1 Method D, RT = 1.634 min, 93.3% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(d, J = 2.2 Hz, 1H), 8.21-8.10 (m, 1H), 7.59 (d, J = 7.1 Hz, 1H),7.50-7.35 (m, 2H), 7.33 (t, J = 8.1 Hz, 1H), 7.28-7.12 (m, 4H), 7.06(dd, J = 8.1, 1.7 Hz, 1H), 5.06 (t, J = 5.5 Hz, 1H), 4.59-4.48 (m, 1H),4.33-4.29 (m, 2H), 3.94-3.81 (m, 1H), 3.75 (t, J = 8.8 Hz, 1H), 3.55 (s,3H), 2.59 (dd, J = 12.2, 7.3 Hz, 1H), 2.14- 1.98 (m, 1H). 36

565.1 Method D, RT = 1.669 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.68(s, 1H), 8.37 (s, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.56-7.37 (m, 3H),7.35-7.15 (m, 5H), 7.15-7.05 (m, 1H), 4.59-4.49 (m, 1H), 3.87 (s, 3H),3.79 (dd, J = 9.7, 6.5 Hz, 1H), 3.69 (t, J = 8.6 Hz, 1H), 2.88 (s, 3H),2.59 (dd, J = 11.7, 7.3 Hz, 1H), 2.13- 1.96 (m, 1H). 37

593.2 Method C, RT = 1.902 min, 97.5% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.97(br. s., 1H), 8.49-8.30 (m, 2H), 7.65 (d, J = 11.7 Hz, 1H), 7.55 (d, J =2.0 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.48-7.22 (m, 7H), 4.59-4.52 (m,1H), 3.83-3.77 (m, 1H), 3.57-3.55 (m, 1H), 3.06-3.02 (m, 1H), 2.87 (s,3H), 2.66-2.58 (m, 1H), 2.14-2.01 (m, 1H), 1.31-1.13 (m, 6H). 38

496.2 Method C, RT = 1.863 min, 92.2% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.67(s, 1H), 8.38 (s, 1H), 8.17 (m, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.49-7.30(m, 4H), 7.30-7.11 (m, 4H), 4.61-4.50 (m, 1H), 4.43 (s, 2H), 3.91 (s,1H), 3.81-3.76 (m, 1H), 3.59-3.56 (m, 1H), 3.04-3.01 (m, 1H), 2.64-2.55(m, 1H), 2.14-2.03 (m, 1H), 1.31-1.13 (m, 6H). 39

602.1 Method C, RT = 1.731 min, 92.6% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.92(br. s., 1H), 8.41 (t, J = 8.4 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H),7.91-7.76 (m, 2H), 7.66 (br. d., J = 12.0 Hz, 1H), 7.57-7.47 (m, 2H),7.43-7.29 (m, 2H), 7.25 (br. d., J = 6.8 Hz, 1H), 5.13 (br. d., J = 1.7Hz, 1H), 4.78-4.65 (m, 1H), 4.27-4.13 (m, 1H), 3.54-3.42 (m, 2H), 3.06(s, 3H), 2.57-2.24 (m, 1H), 2.35-2.31 (m, 1H). 40

544.2 Method D, RT = 1.851 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(d, J = 2.0 Hz, 1H), 8.17 (t, J = 8.9 Hz, 1H), 8.12 (dd, J = 7.9, 1.1Hz, 1H), 7.82- 7.75 (m, 1H), 7.73-7.64 (m, 1H), 7.54- 7.36 (m, 3H),7.34-7.25 (m, 2H), 7.23- 7.09 (m, 2H), 4.57-4.52 (m, 1H), 3.84- 3.74 (m,1H), 3.59 (t, J = 9.0 Hz, 1H), 3.06-3.02 (m, 1H), 2.82 (s, 3H), 2.65-2.56 (m, 1H), 2.13-2.00 (m, 1H), 1.31- 1.06 (m, 6H). 41

506.1 Method D, RT = 1.825 min, 97.2% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.15(s, 1H), 7.78-7.50 (m, 5H), 7.50-7.43 (m, 1H), 7.43-7.31 (m, 2H),7.30-7.16 (m, 2H), 6.85 (d, J = 7.3 Hz, 1H), 5.16 (t, J = 5.4 Hz, 1H),4.65-4.52 (m, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.99-3.83 (m, 1H),3.83-3.72 (m, 1H), 2.64-2.53 (m, 1H), 2.20-2.05 (m, 1H). 42

568.1 Method C, RT = 1.598 min, 98.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.61(br. s., 1H), 8.22-8.07 (m, 2H), 7.88- 7.73 (m, 2H), 7.58-7.49 (m, 1H),7.45- 7.25 (m, 3H), 7.23-7.15 (m, 1H), 7.09 (d, J = 7.1 Hz, 1H),4.76-4.64 (m, 1H), 4.24-4.13 (m, 1H), 3.99-3.87 (m, 1H), 3.49-3.45 (m,2H), 3.05 (s, 3H), 2.57- 2.55 (m, 1H), 2.26-2.21 (m, 1H). 43

591.2 Method C, RT = 2.008 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.08-8.82 (m, 2H), 8.42 (t, J = 8.3 Hz, 1H), 7.71-7.61 (m, 1H), 7.52 (d, J =8.3 Hz, 1H), 7.48-7.36 (m, 2H), 7.36-7.20 (m, 5H), 7.12 (s, 1H),4.65-4.52 (m, 1H), 3.83 (td, J = 9.2, 6.1 Hz, 1H), 3.66 (t, J = 9.2 Hz,1H), 2.86 (s, 3H), 2.67-2.58 (m, 1H), 2.19-2.03 (m, 1H), 2.00-1.90 (m,1H), 1.04-0.83 (m, 2H), 0.79-0.62 (m, 2H). 44

545.2 Method C, RT = 1.776 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.15 (t, J = 8.9 Hz, 1H), 7.51 (s,1H), 7.49-7.30 (m, 6H), 7.25-7.15 (m, 2H), 4.98 (m, 1H), 4.61-4.51 (m,1H), 3.89 (td, J = 9.5, 6.6 Hz, 1H), 3.77 (t, J = 8.7 Hz, 1H), 2.58 (dd,J = 13.6, 5.7 Hz, 1H), 2.16- 2.01 (m, 1H), 1.85 (s, 3H), 1.38 (d, J =7.1 Hz, 3H). 45

542.2 Method C, RT = 1.778 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(s, 1H), 8.17 (t, J = 8.9 Hz, 1H), 7.98 (dd, J = 12.8, 7.7 Hz, 1H),7.68-7.59 (m, 1H), 7.59-7.47 (m, 2H), 7.45-7.26 (m, 4H), 7.25-7.13 (m,2H), 4.60-4.49 (m, 1H), 3.80 (d, J = 6.1 Hz, 1H), 3.61-3.52 (m, 1H),3.07-2.99 (m, 1H), 2.59-2.55 (m, 1H), 2.28-1.99 (m, 1H), 1.33 (d, J =13.4 Hz, 6H), 1.23-1.10 (m, 6H). 46

577.2 Method C, RT = 1.716 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(d, J = 2.4 Hz, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.93 (dd, J = 12.3, 8.2Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.42 (dd, J= 11.2, 2.4 Hz, 1H), 7.39- 7.32 (m, 1H), 7.32-7.24 (m, 2H), 7.24- 7.06(m, 3H), 4.63-4.50 (m, 1H), 3.83 (td, J = 9.6, 6.7 Hz, 1H), 3.67 (t, J =8.8 Hz, 1H), 2.65-2.56 (m, 1H), 2.16-2.05 (m, 1H), 2.00-1.90 (m, 1H),1.34 (d, J = 13.2 Hz, 3H), 1.33 (d, J = 13.2 Hz, 3H), 0.98-0.84 (m, 2H),0.82-0.65 (m, 2H). 47

560.2 Method C, RT = 1.760 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.80(br. s., 1H), 8.62 (s, 1H), 8.25-8.05 (m, 2H), 7.68-7.51 (m, 2H),7.51-7.35 (m, 2H), 7.31-7.10 (m, 3H), 6.93-6.91 (m, 1H), 4.59-4.50 (m,1H), 3.77 (d, J = 6.4 Hz, 1H), 3.56 (d, J = 8.3 Hz, 1H), 3.10 (s, 3H),3.04-2.98 (m, 1H), 2.65-2.62 (m, 1H), 2.18-1.96 (m, 1H), 1.39-1.15 (m,6H). 48

558.2 Method C, RT = 1.861 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 10.5(br. s., 1H), 8.64 (d, J = 2.7 Hz, 1H), 8.31- 8.04 (m, 2H), 7.71 (dd, J= 7.6, 1.7 Hz, 1H), 7.47-7.35 (m, 2H), 7.35-7.27 (m, 1H), 7.26-7.14 (m,3H), 7.10 (br. s., 1H), 4.64-4.50 (m, 1H), 3.81 (td, J = 9.6, 6.5 Hz,1H), 3.65 (t, J = 9.0 Hz, 1H), 3.20 (s, 3H), 2.66-2.57 (m, 1H), 2.15-2.02 (m, 1H), 2.01-1.88 (m, 1H), 1.03- 0.83 (m, 2H), 0.78-0.55 (m, 2H).49

519.1 Method C, RT = 1.469 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.45(s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.00- 7.87 (m, 2H), 7.82 (dd, J =9.0, 2.7 Hz, 1H), 7.71-7.54 (m, 3H), 7.44-7.31 (m, 2H), 7.31-7.22 (m,1H), 4.66-4.56 (m, 1H), 4.01-3.85 (m, 1H), 3.84-3.76 (m, 1H), 2.59-2.86(m, 1H), 2.21-2.11 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H). 50

503.2 Method D, RT = 1.498 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(d, J = 1.7 Hz, 1H), 8.20-8.08 (m, 1H), 7.62 (s, 1H), 7.53-7.28 (m, 6H),7.25- 7.16 (m, 2H), 4.62-4.49 (m, 1H), 4.17 (q, J = 6.6 Hz, 1H),3.94-3.85 (m, 1H), 3.82-3.72 (m, 1H), 3.34 (br. s., 2H), 2.65-2.55 (m,1H), 2.13-2.02 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H). 51

568.2 Method C, RT = 1.709 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.99(s, 1H), 7.99-7.86 (m, 1H), 7.73-7.57 (m, 2H), 7.57-7.44 (m, 2H),7.42-7.32 (m, 2H), 7.32-7.14 (m, 3H), 6.81 (d, J = 7.3 Hz, 1H),4.61-4.49 (m, 1H), 3.94- 3.84 (m, 1H), 3.83-3.71 (m, 1H), 2.61- 2.53 (m,1H), 2.18-2.05 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H). 52

538.1 Method D, RT = 1.774 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.61(d, J = 2.2 Hz, 1H), 8.23-8.04 (m, 2H), 7.87-7.63 (m, 2H), 7.49 (dd, J =7.5, 1.1 Hz, 1H), 7.42 (dd, J = 11.1, 2.3 Hz, 1H), 7.35 (d, J = 9.0 Hz,2H), 7.24-7.11 (m, 2H), 4.63-4.50 (m, 1H), 3.83-3.75 (m, 1H), 3.75-3.67(m, 1H), 3.05 (s, 3H), 2.63-2.55 (m, 1H), 2.19-2.08 (m, 1H). 53

536.1 Method C, RT = 1.594 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65-8.57 (m, 1H), 8.19-8.12 (m, 1H), 7.96- 7.86 (m, 1H), 7.69-7.56 (m, 2H),7.46- 7.37 (m, 4H), 7.24-7.17 (m, 2H), 4.64- 4.53 (m, 1H), 3.84-3.67 (m,2H), 2.66- 2.57 (m, 1H), 2.19-2.06 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H).54

516.2 Method C, RT = 1.485 min, 98.5% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.49(s, 1H), 8.14 (dd, J = 7.8, 1.5 Hz, 1H), 7.91-7.71 (m, 2H), 7.51 (dd, J= 7.8, 1.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.38- 7.22 (m, 3H),6.92-6.74 (m, 2H), 6.56 (d, J = 7.3 Hz, 1H), 4.56-4.50 (m, 1H),3.99-3.83 (m, 1H), 3.83-3.75 (m, 1H), 3.71 (s, 3H), 3.06 (s, 3H),2.61-2.54 (m, 1H), 2.20-2.01 (m, 1H). 55

571.2 Method C, RT = 1.589 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.86(s, 1H), 9.13 (d, J = 6.8 Hz, 1H), 8.49 (s, 1H), 8.22 (dd, J = 10.4, 1.8Hz, 1H), 8.00- 7.84 (m, 1H), 7.72-7.56 (m, 2H), 7.46- 7.30 (m, 2H), 7.27(t, J = 7.8 Hz, 1H), 4.74-4.61 (m, 1H), 4.00-3.87 (m, 1H), 3.86-3.78 (m,1H), 2.66-2.56 (m, 1H), 2.30-2.17 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H). 56

537.2 Method C, RT = 1.475 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.44(s, 1H), 8.68 (d, J = 6.8 Hz, 1H), 8.19 (s, 1H), 8.05 (dd, J = 10.0, 2.2Hz, 1H), 7.98- 7.88 (m, 1H), 7.67-7.40 (m, 2H), 7.47- 7.31 (m, 2H),7.29-7.21 (m, 1H), 4.70- 4.62 (m, 1H), 3.98-3.84 (m, 1H), 3.84- 3.74 (m,1H), 2.63-2.55 (m, 1H), 2.27- 2.13 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H).57

570.2 Method C, RT = 1.728 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(d, J = 2.0 Hz, 1H), 8.41 (t, J = 8.6 Hz, 1H), 7.98-7.85 (m, 1H),7.72-7.55 (m, 3H), 7.51 (d, J = 8.3 Hz, 1H), 7.42-7.30 (m, 3H),7.30-7.22 (m, 1H), 4.65-4.54 (m, 1H), 3.96-3.85 (m, 1H), 3.79-3.45 (m,1H), 2.65-2.57 (m, 1H), 2.16-2.02 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H). 58

537.2 Method C, RT = 1.671 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.75(br. s., 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.14 (t, J = 8.9 Hz, 1H),7.78-7.67 (m, 2H), 7.46-7.23 (m, 5H), 7.23-7.16 (m, 1H), 4.61-4.50 (m,1H), 4.27 (br. s., 1H), 3.96-3.85 (m, 1H), 3.82-3.75 (m, 1H), 2.93-2.89(m, 3H), 2.62-2.54 (m, 1H), 2.15-2.04 (m, 1H). 59

537.2 Method C, RT = 1.672 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.76(br. s., 1H), 8.26-8.06 (m, 2H), 7.81- 7.64 (m, 2H), 7.51-7.29 (m, 5H),7.20 (ddd, J = 9.0, 2.4, 1.3 Hz, 1H), 4.56 (dd, J = 17.9, 8.3 Hz, 1H),4.28 (br. s., 1H), 3.92-3.90 (m, 1H), 3.79 (t, J = 8.3 Hz, 1H),2.93-2.89 (m, 3H), 2.64-2.53 (m, 1H), 2.16-2.01 (m, 1H). 60

576.3 Method C, RT = 2.041 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.91(d, J = 2.9 Hz, 1H), 8.43 (t, J = 8.6 Hz, 1H), 7.98 (dd, J = 12.7, 7.8Hz, 1H), 7.71- 7.60 (m, 2H), 7.60-7.47 (m, 3H), 7.37 (dd, J = 7.0, 3.5Hz, 1H), 7.35-7.23 (m, 3H), 4.63-4.51 (m, 1H), 3.86-3.74 (m, 1H), 3.58(t, J = 8.7 Hz, 1H), 3.09-2.99 (m, 1H), 2.66-2.56 (m, 1H), 2.17-2.02 (m,1H), 1.34 (d, J = 13.2 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H), 1.20 (d, J =6.8 Hz, 3H). 61

543.2 Method C, RT = 1.774 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.44(s, 1H), 8.67 (d, J = 5.9 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.04 (dd, J= 10.1, 2.2 Hz, 1H), 8.01-7.91 (m, 1H), 7.68-7.59 (m, 1H), 7.59-7.48 (m,2H), 7.37 (dd, J = 6.4, 4.2 Hz, 1H), 7.31 (d, J = 1.0 Hz, 2H), 4.60-4.55(m, 1H), 3.83-3.75 (m, 1H), 3.64-3.59 (m, 1H), 3.13-3.05 (m, 1H),2.63-2.54 (m, 1H), 2.29-2.20 (m, 1H), 1.34 (d, J = 13.2 Hz, 6H), 1.19(d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H). 62

524.2 Method C, RT = 1.607 min, 99.6% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.74(br. s., 1H), 8.90 (d, J = 1.5 Hz, 1H), 8.41 (d, J = 1.2 Hz, 1H),7.98-7.89 (m, 1H), 7.67-7.43 (m, 3H), 7.41-7.20 (m, 3H), 7.13 (d, J =1.7 Hz, 1H), 4.64-4.54 (m, 1H), 3.83 (td, J = 9.5, 6.7 Hz, 1H), 3.73-3.65 (m, 1H), 2.65-2.56 (m, 1H), 2.24- 2.13 (m, 1H), 2.03-1.93 (m, 1H),1.34 (d, J = 13.2 Hz, 6H), 1.02-0.82 (m, 2H), 0.80-0.65 (m, 2H). 63

520.2 Method C, RT = 1.517 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.83(br. s., 1H), 8.90 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 7.99-7.85 (m, 1H),7.73-7.53 (m, 3H), 7.51-7.30 (m, 2H), 7.30-7.20 (m, 1H), 4.67-4.55 (m,1H), 3.95-3.87 (m, 1H), 3.80-3.77 (m, 1H), 2.64-2.56 (m, 1H), 2.28-2.00(m, 1H), 1.52 (d, J = 13.2 Hz, 6H). 64

553.3 Method C, RT = 1.742 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.79(s, 1H), 8.59 (s, 1H), 8.08 (dd, J = 8.8, 2.2 Hz, 2H), 7.96-7.86 (m,1H), 7.79 (d, J = 8.8 Hz, 1H), 7.72-7.55 (m, 2H), 7.45- 7.31 (m, 2H),7.31-7.23 (m, 1H), 4.70- 4.59 (m, 1H), 3.98-3.84 (m, 1H), 3.84- 3.74 (m,1H), 2.65-2.55 (m, 1H), 2.28- 2.08 (m, 1H), 1.53 (d, J = 13.2 Hz, 6H).65

514.3 Method C, RT = 1.496 min, 97.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.48(s, 1H), 7.98-7.88 (m, 1H), 7.72-7.52 (m, 2H), 7.43-7.19 (m, 5H),6.88-6.77 (m, 2H), 6.55 (d, J = 7.3 Hz, 1H), 4.58- 4.49 (m, 1H),3.93-3.83 (m, 1H), 3.77- 3.74 (m, 1H), 3.71 (s, 3H), 2.60-2.54 (m, 1H),2.23-1.99 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H). 66

571.2 Method C, RT = 1.815 min, 96.2% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.41(t, J = 8.2 Hz, 1H), 8.18 (br. s., 1H), 7.80- 7.69 (m, 2H), 7.67 (d, J =10.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.46-7.29 (m, 4H), 7.29-7.06 (m,1H), 4.65-4.53 (m, 1H), 3.98-3.86 (m, 1H), 3.80 (t, J = 8.9 Hz, 1H),2.93-2.89 (m, 3H), 2.64-2.55 (m, 1H), 2.16-2.04 (m, 1H). 67

565.2 Method C, RT = 1.804 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.45(s, 1H), 8.69 (d, J = 6.4 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 10.3 Hz,1H), 7.89 (dd, J = 11.5, 7.3 Hz, 1H), 7.64 (quin, J = 7.8 Hz, 2H),7.48-7.26 (m, 2H), 7.17 (t, J = 7.9 Hz, 1H), 4.70-4.59 (m, 1H), 3.96-3.85 (m, 1H), 3.85-3.74 (m, 1H), 2.63- 2.54 (m, 1H), 2.29-2.11 (m, 1H),1.80- 1.60 (m, 4H), 0.93-0.88 (m, 6H). 68

598.2 Method C, RT = 2.038 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.91(br. s., 1H), 8.41 (t, J = 8.6 Hz, 1H), 7.97- 7.83 (m, 1H), 7.75-7.56(m, 3H), 7.51 (d, J = 8.8 Hz, 1H), 7.42-7.23 (m, 3H), 7.22-7.11 (m, 1H),4.63-4.51 (m, 1H), 3.96-3.87 (m, 1H), 3.81-3.76 (m, 1H), 2.64-2.56 (m,1H), 2.17-2.02 (m, 1H), 1.80-1.60 (m, 4H), 0.93-0.88 (m, 6H). 69

586.2 Method C, RT = 1.903 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.70(s, 1H), 8.22 (t, J = 9.2 Hz, 1H), 7.92 (dd, J = 12.5, 7.8 Hz, 1H),7.73-7.55 (m, 2H), 7.49-7.30 (m, 3H), 7.30-7.23 (m, 1H), 7.23-7.09 (m,2H), 4.63-4.52 (m, 1H), 4.00-3.84 (m, 1H), 3.80-3.75 (m, 1H), 2.64-2.56(m, 1H), 2.18-2.01 (m, 1H), 1.52 (d, J = 13.2 Hz, 6H). 70

554.2 Method C, RT = 1.663 min, 99.2% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(d, J = 5.4 Hz, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.79-7.68 (m, 1H),7.52-7.36 (m, 2H), 7.35-7.24 (m, 1H), 7.24-7.08 (m, 4H), 4.61-4.50 (m,1H), 3.94-3.82 (m, 1H), 3.79-3.67 (m, 1H), 2.59 (dd, J = 12.7, 7.6 Hz,1H), 2.13-2.01 (m, 1H), 1.86-1.59 (m, 6H) 71

532.3 Method D, RT = 1.383 min, 98.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.24(s, 1H), 7.92 (dd, J = 12.2, 8.1 Hz, 1H), 7.84 (t, J = 9.3 Hz, 1H),7.74-7.55 (m, 2H), 7.37 (d, J = 6.8 Hz, 2H), 7.30-7.22 (m, 1H), 6.97 (d,J = 7.1 Hz, 1H), 6.87 (dd, J = 12.2, 2.6 Hz, 1H), 6.72 (dd, J = 8.9, 1.8Hz, 1H), 4.61-4.48 (m, 1H), 3.95- 3.84 (m, 1H), 3.82-3.59 (m, 1H), 3.74(s, 3H), 2.62-2.55 (m, 1H), 2.15-2.02 (m, 1H), 1.52 (d, J = 13.2 Hz,6H). 72

588.2 Method C, RT = 1.794 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.95(dd, J = 8.2, 2.5 Hz, 1H), 8.41 (t, J = 8.2 Hz, 1H), 7.76-7.65 (m, 2H),7.53-7.43 (m, 2H), 7.38-7.28 (m, 2H), 7.23-7.16 (m, 2H), 4.62-4.54 (m,1H), 3.94-3.83 (m, 1H), 3.81-3.70 (m, 1H), 2.64-2.53 (m, 1H), 2.16-2.02(m, 1H), 1.76-1.64 (m, 6H). 73

588.2 (M + NH₄)⁺ Method D, RT = 1.647 min, 100% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.94 (d, J = 2.9 Hz, 1H), 8.84 (d, J = 4.2 Hz, 1H), 8.42(t, J = 8.3 Hz, 1H), 7.87-7.86 (m, 1H), 7.73-7.62 (m, 2H), 7.52 (d, J =8.6 Hz, 1H), 7.43-7.25 (m, 3H), 4.65- 4.52 (m, 1H), 3.98-3.86 (m, 1H),3.82- 3.70 (m, 1H), 2.64-2.56 (m, 1H), 2.16- 2.04 (m, 1H), 1.62 (d, J =13.2 Hz, 6H). 74

554.2 (M + NH₄)⁺ Method D, RT = 1.498 min, 100% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.84 (br d, J = 4.2 Hz, 1H), 8.64 (s, 1H), 8.15 (t, J = 8.9Hz, 1H), 7.86 (dd, J = 3.5, 7.5 Hz, 1H), 7.70-7.61 (m, 1H), 7.42 (dd, J= 2.4, 11.0 Hz, 1H), 7.37 (br d, J = 8.1 Hz, 1H), 7.32-7.24 (m, 1H),7.20 (br d, J = 7.6 Hz, 2H), 4.62-4.50 (m, 1H), 3.95- 3.84 (m, 1H),3.82-3.71 (m, 1H), 2.64- 2.56 (m, 1H), 2.13-2.00 (m, 1H), 1.62 (d, J =13.4 Hz, 6H). 75

564.2 Method C, RT = 1.723 min, 99.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.62(d, J = 2.4 Hz, 1H), 8.16 (t, J = 8.9 Hz, 1H), 7.87 (ddd, J = 11.6, 7.5,1.7 Hz, 1H), 7.70-7.53 (m, 2H), 7.43 (dd, J = 11.0, 2.4 Hz, 1H), 7.36(ddd, J = 7.5, 3.6, 1.6 Hz, 1H), 7.33-7.26 (m, 2H), 7.23- 7.16 (m, 2H),4.64-4.50 (m, 1H), 3.84- 3.74 (m, 1H), 3.73-3.63 (m, 1H), 2.66- 2.57 (m,1H), 2.19-2.01 (m, 1H), 1.71 (m, 4H), 0.93-0.88 (m, 6H). 76

570.2 Method C, RT = 1.867 min, 98.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.91(d, J = 2.9 Hz, 1H), 8.41 (m, 1H), 7.91 (ddd, J = 13.0, 7.6, 1.2 Hz,1H), 7.73- 7.56 (m, 3H), 7.52 (d, J = 9.5 Hz, 1H), 7.46-7.38 (m, 3H),7.35 (d, J = 7.1 Hz, 1H), 4.68-4.55 (m, 1H), 3.85-3.76 (m, 1H),3.74-3.66 (m, 1H), 2.67-2.59 (m, 1H), 2.21-2.10 (m, 1H), 1.49 (d, J =13.5 Hz, 6H). 77

586.2 Method C, RT = 1.781 min, 99.8% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.95(t, J = 3.2 Hz, 1H), 8.42 (t, J = 8.2 Hz, 1H), 8.01-7.90 (m, 1H),7.70-7.58 (m, 3H), 7.55-7.47 (m, 2H), 7.39-7.21 (m, 3H), 4.63-4.53 (m,1H), 3.97-3.85 (m, 1H), 3.82-3.70 (m, 1H), 2.64-2.55 (m, 1H), 2.17-2.03(m, 1H), 1.48 (d, J = 12.8 Hz, 3H), 1.46 (d, J = 12.8 Hz, 3H). 78

568.1 Method C, RT = 1.691 min, 99.8% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(dd, J = 6.1, 2.4 Hz, 1H), 8.17 (t, J = 8.9 Hz, 1H), 7.98-7.88 (m, 1H),7.70-7.57 (m, 2H), 7.54-7.39 (m, 3H), 7.29 (td, J = 3.5, 7.1 Hz, 1H),7.24-7.13 (m, 2H), 4.63-4.49 (m, 1H), 3.87-3.76 (m, 1H), 3.73-3.64 (m,1H), 2.66-2.57 (m, 1H), 2.16-2.01 (m, 1H), 1.52-1.44 (m, 6H). 79

500.1 Method C, RT = 1.763 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.73(s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.33 (s, 1H), 8.15 (t, J = 8.8 Hz,1H), 7.90 (s, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.48-7.33 (m, 2H),7.29-7.11 (m, 2H), 4.55 (dd, J = 18.1, 8.6 Hz, 1H), 3.92-3.84 (m, 1H),3.81-3.72 (m, 1H), 2.61 (m, 1H), 2.12- 2.00 (m, 1H). 80

602.1 Method C, RT = 1.821 min, 99.5% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.94(dd, J = 5.9, 2.9 Hz, 1H), 8.42 (m, 1H), 7.99-7.89 (m, 1H), 7.72-7.55(m, 3H), 7.54-7.44 (m, 3H), 7.35 (dd, J = 7.1, 2.9 Hz, 1H), 7.32-7.24(m, 1H), 4.65-4.53 (m, 1H), 3.87-3.78 (m, 1H), 3.74-3.67 (m, 1H), 2.63(dt, J = 6.4, 5.1 Hz, 1H), 2.17-2.03 (m, 1H), 1.50-1.45 (m, 6H). 81

552.2 Method D, RT = 2.358 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(br. s., 1H), 8.15 (t, J = 8.8 Hz, 1H), 7.94 (dd, J = 12.5, 1.5 Hz, 1H),7.69-7.58 (m, 2H), 7.55-7.48 (m, 1H), 7.42 (dd, J = 11.3, 2.3 Hz, 1H),7.32 (d, J = 7.8 Hz, 1H), 7.30-7.26 (m, 1H), 7.22-7.16 (m, 2H), 4.56 (s,1H), 3.96-3.83 (m, 1H), 3.83-3.70 (m, 1H), 2.61-2.57 (m, 1H), 2.13-2.01(m, 1H), 1.48 (d, J = 12.8 Hz, 3H), 1.46 (d, J = 12.8 Hz, 3H). 82

508.1 Method C, RT = 1.834 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(d, J = 1.0 Hz, 1H), 8.15 (t, J = 8.8 Hz, 1H), 7.63-7.50 (m, 2H),7.50-7.29 (m, 5H), 7.24-7.15 (m, 1H), 7.11 (d, J = 7.3 Hz, 1H), 5.10 (t,J = 4.9 Hz, 1H), 4.81- 4.62 (m, 1H), 4.29-4.12 (m, 1H), 3.49- 3.47 (m,2H), 2.55-2.52 (m, 1H), 2.31- 2.21 (m, 1H). 83

586.2 Method C, RT = 2.031 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.66(d, J = 2.5 Hz, 1H), 8.15 (t, J = 8.8 Hz, 1H), 7.89-7.80 (m, 1H), 7.75(t, J = 7.8 Hz, 1H), 7.63-7.53 (m, 2H), 7.43 (dd, J = 11.3, 2.3 Hz, 1H),7.31-7.13 (m, 4H), 4.62-4.50 (m, 1H), 3.97-3.94 (m, 1H), 3.81-3.73 (m,1H), 2.63-2.55 (m, 1H), 2.17-2.05 (m, 1H), 1.54 (d, J = 13.6 Hz, 3H),1.52 (d, J = 13.6 Hz, 3H). 84

555.2 (M + NH₄)⁺ Method C, RT = 1.369 min, 92.6% ¹H NMR (400 MHz,DMSO-d₆) δ = 9.47 (s, 1H), 8.97 (d, J = 5.6 Hz, 1H), 8.66 (d, J = 2.4Hz, 1H), 8.15 (t, J = 8.9 Hz, 1H), 7.48-7.34 (m, 3H), 7.25-7.17 (m, 2H),4.62-4.54 (m, 1H), 3.96-3.85 (m, 1H), 3.78 (t, J = 8.6 Hz, 1H),2.63-2.54 (m, 1H), 2.15-2.04 (m, 1H), 1.69 (d, J = 13.7 Hz, 6H). 85

570.2 Method C, RT = 1.722 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.68-8.58 (m, 1H), 8.15 (t, J = 8.8 Hz, 1H), 7.76-7.65 (m, 1H), 7.52-7.35 (m,3H), 7.25-7.15 (m, 3H), 7.13-7.06 (m, 1H), 4.59-4.48 (m, 1H), 3.91-3.81(m, 1H), 3.78-3.67 (m, 1H), 2.55-2.52 (m, 1H), 2.13-2.01 (m, 1H),1.73-1.61 (m, 6H). 86

604.1 Method C, RT = 1.834 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.98-8.91 (m, 1H), 8.45-8.38 (m, 1H), 7.76- 7.62 (m, 2H), 7.52 (br. d., J =9.3 Hz, 1H), 7.48-7.40 (m, 2H), 7.36-7.30 (m, 1H), 7.24-7.18 (m, 1H),7.11 (d, J = 6.6 Hz, 1H), 4.62-4.52 (m, 1H), 3.92-3.83 (m, 1H),3.78-3.70 (m, 1H), 2.64-2.56 (m, 1H), 2.14-2.06 (m, 1H), 1.72-1.64 (m,6H). 87

602.2 Method C, RT = 1.795 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(dd, J = 1.7, 8.8 Hz, 1H), 8.15 (t, J = 8.9 Hz, 1H), 7.88 (dd, J = 7.3,12.7 Hz, 1H), 7.70-7.53 (m, 3H), 7.43 (dd, J = 2.4, 11.0 Hz, 1H),7.38-7.30 (m, 2H), 7.24- 7.10 (m, 2H), 4.61-4.52 (m, 1H), 3.96- 3.85 (m,1H), 3.81-3.71 (m, 1H), 2.61- 2.54 (m, 1H), 2.17-2.03 (m, 1H), 1.64-1.48 (m, 6H). 88

636.2 Method C, RT = 1.919 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.94(dd, J = 2.9, 8.6 Hz, 1H), 8.41 (m, 1H), 7.92-7.82 (m, 1H), 7.71-7.54(m, 4H), 7.51 (d, J = 8.8 Hz, 1H), 7.39-7.31 (m, 3H), 4.63-4.53 (m, 1H),3.96-3.87 (m, 1H), 3.81-3.73 (m, 1H), 2.63-2.57 (m, 1H), 2.18-2.06 (m,1H), 1.61-1.50 (m, 6H). 89

592.2 Method C, RT = 1.872 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.96-8.89 (m, 1H), 8.41 (t, J = 8.3 Hz, 1H), 8.03-7.93 (m, 1H), 7.71-7.49 (m,4H), 7.39-7.26 (m, 3H), 7.14-7.07 (m, 1H), 4.58-4.49 (m, 1H), 3.87-3.78(m, 1H), 3.74-3.67 (m, 1H), 2.63-2.54 (m, 1H), 2.13-2.02 (m, 1H),1.60-1.50 (m, 1H), 1.45 (d, J = 13.4 Hz, 3H), 1.42 (d, J = 13.4 Hz, 3H),0.79-0.72 (m, 1H), 0.71- 0.61 (m, 3H). 90

614.2 Method C, RT = 1.768 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.94(d, J = 2.0 Hz, 1H), 8.40 (t, J = 8.3 Hz, 1H), 8.01-7.89 (m, 1H),7.72-7.58 (m, 3H), 7.51 (m, 1H), 7.40 (m, 1H), 7.34- 7.18 (m, 3H),4.71-4.58 (m, 1H), 4.33 (m, 1H), 3.48 (dd, J = 10.5, 3.9 Hz, 1H),3.40-3.36 (m, 1H), 3.24 (s, 3H), 2.49- 2.44 (m, 1H), 2.37-2.23 (m, 1H),1.62- 1.36 (m, 6H). 91

586.2 Method C, RT = 1.778 min, 99.8% ¹H NMR (400 MHz, DMSO-d₆) δ =8.71- 8.59 (m, 1H), 8.22-8.12 (m, 1H), 7.93- 7.90 (m, 1H), 7.83-7.75 (m,1H), 7.70- 7.58 (m, 2H), 7.48-7.33 (m, 3H), 7.24- 7.14 (m, 2H), 4.62 (d,J = 1.2 Hz, 1H), 3.96-3.84 (m, 1H), 3.81-3.71 (m, 1H), 2.65-2.58 (m,1H), 2.10-2.04 (m, 1H), 1.67-1.33 (m, 6H). 92

620.2 Method C, RT = 1.911 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.00-8.89 (m, 1H), 8.47-8.37 (m, 1H), 7.95- 7.86 (m, 1H), 7.83-7.74 (m, 1H),7.71- 7.60 (m, 3H), 7.55-7.48 (m, 1H), 7.45- 7.36 (m, 2H), 7.35-7.32 (m,1H), 4.75- 4.43 (m, 1H), 3.96-3.84 (m, 1H), 3.81- 3.71 (m, 1H),2.66-2.58 (m, 1H), 2.10- 2.04 (m, 1H), 1.60-1.48 (m, 6H). 93

589.2 (M + NH₄)⁺ Method C, RT = 1.532 min, 94.1% ¹H NMR (400 MHz,DMSO-d₆) δ = 9.47 (s, 1H), 9.03-8.85 (m, 2H), 8.42 (t, J = 8.2 Hz, 1H),7.67 (br. d., J = 11.5 Hz, 1H), 7.53 (s, 1H), 7.48-7.30 (m, 3H), 4.60(td, J = 10.2, 8.0 Hz, 1H), 4.01- 3.87 (m, 1H), 3.79 (br. t., 8.8 Hz,1H), 2.65-2.55 (m, 1H), 2.18-2.04 (m, 1H), 1.69 (d, J = 13.7 Hz, 6H). 94

620.2 Method C, RT = 1.932 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.95(d, J = 3.2 Hz, 1H), 8.41 (t, J = 8.4 Hz, 1H), 7.90-7.80 (m, 1H), 7.76(t, J = 7.9 Hz, 1H), 7.67 (dd, J = 1.8, 11.6 Hz, 1H), 7.63-7.55 (m, 2H),7.52 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.29-7.19 (m, 2H),4.64-4.55 (m, 1H), 3.96-3.87 (m, 1H), 3.83-3.74 (m, 1H), 2.99-2.87 (m,1H), 2.64-2.56 (m, 1H), 2.16-2.06 (m, 1H), 1.60-1.48 (m, 6H). 95

568.2 Method C, RT = 1.608 min, 99% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(br. s., 1H), 8.16 (t, J = 8.8 Hz, 1H), 7.98- 7.87 (m, 1H), 7.74-7.57(m, 3H), 7.43 (dd, J = 11.2, 2.4 Hz, 1H), 7.32-7.10 (m, 4H), 6.59 (t, J= 52.4 Hz, 1H), 4.60-4.50 (m, 1H), 3.95-3.85 (m, 1H), 3.81-3.71 (m, 1H),2.62-2.55 (m, 1H), 2.17-2.03 (m, 1H), 1.50 (d, J = 13.2 Hz, 3H), 1.44(d, J = 13.2 Hz, 3H). 96

532.2 Method C, RT = 1.813 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(d, J = 1.5 Hz, 1H), 8.16 (m, 1H), 8.04- 7.92 (m, 1H), 7.69-7.54 (m,2H), 7.43 (dd, J = 11.1, 2.3 Hz, 1H), 7.36-7.26 (m, 2H), 7.24-7.13 (m,3H), 4.59-4.45 (m, 1H), 3.89-3.78 (m, 1H), 3.69-3.55 (m, 1H), 2.62-2.54(m, 1H), 2.12 (m, 3H), 2.10-1.99 (m, 1H), 1.45 (br. d., J = 13.4 Hz,3H), 1.36 (br. d., J = 13.4 Hz, 3H). 97

585.2 Method C, RT = 1.809 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.95(d, J = 2.7 Hz, 1H), 8.42 (t, J = 8.4 Hz, 1H), 8.02-7.84 (m, 1H),7.81-7.74 (m, 1H), 7.70-7.62 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H),7.54-7.48 (m, 1H), 7.46 (dd, J = 6.8, 1.7 Hz, 1H), 7.42 (dd, J = 7.2,1.7 Hz, 1H), 7.40-7.32 (m, 1H), 4.68-4.56 (m, 1H), 4.45 (s, 2H),4.00-3.88 (m, 1H), 3.85-3.77 (m, 1H), 2.66-2.56 (m, 1H), 2.18-2.05 (m,1H). 98

586.2 Method C, RT = 1.764 min, 99.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(br. s., 1H), 8.42 (m, 1H), 7.94-7.90 (m, 1H), 7.71-7.57 (m, 3H),7.56-7.49 (m, 1H), 7.49-7.41 (m, 1H), 7.41-7.26 (m, 3H), 4.67-4.53 (m,1H), 3.88-3.79 (m, 1H), 3.76-3.66 (m, 1H), 2.67-2.56 (m, 1H), 2.20-2.05(m, 1H), 1.57-1.48 (m, 6H). 99

552.2 Method C, RT = 1.595 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(br. s., 1H), 8.17 (t, J = 8.9 Hz, 1H), 7.95- 7.90 (m, 1H), 7.71-7.57(m, 2H), 7.50- 7.30 (m, 4H), 7.25-7.09 (m, 2H), 4.65- 4.49 (m, 1H), 3.82(dt, J = 9.4, 6.4 Hz, 1H), 3.74-3.61 (m, 1H), 2.66-2.56 (m, 1H),2.15-2.03 (m, 1H), 1.57-1.48 (m, 6H). 100

599.2 Method C, RT = 1.857 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(d, J = 2.7 Hz, 1H), 8.85 (dd, J = 4.6, 1.2 Hz, 1H), 8.42 (m, 1H),7.86-8.82 (m, 1H), 7.70-7.60 (m, 2H), 7.55-7.47 (m, 1H), 7.42-7.29 (m,2H), 7.24-7.16 (m, 1H), 4.64-4.52 (m, 1H), 3.96-3.87 (m, 1H), 3.81-3.73(m, 1H), 2.65-2.58 (m, 1H), 2.16-1.81 (m, 5H), 1.02-0.85 (m, 6H). 101

583.1 (M + NH₄)⁺ Method C, RT = 1.746 min, 100% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.69- 8.56 (m, 1H), 8.15 (t, J = 8.9 Hz, 1H), 8.04-7.91 (m,1H), 7.76-7.59 (m, 2H), 7.49-7.32 (m, 3H), 7.29-7.10 (m, 3H), 4.62-4.51(m, 1H), 3.97-3.61 (m, 4H), 2.57-2.52 (m, 1H), 2.14-2.01 (m, 1H), 1.44(d, J = 14.4 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 102

598.2 Method C, RT = 1.965 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.96(d, J = 2.7 Hz, 1H), 8.46 (t, J = 8.3 Hz, 1H), 7.97-7.86 (m, 1H),7.72-7.57 (m, 3H), 7.53 (d, J = 8.8 Hz, 1H), 7.42-7.30 (m, 2H),7.30-7.22 (m, 2H), 4.65 (d, J = 9.0 Hz, 1H), 3.88 (br. d., J = 9.3 Hz,1H), 3.45 (br. d., J = 9.3 Hz, 1H), 1.53 (d, J = 13.2 Hz, 6H), 1.22 (s,3H), 1.06 (s, 3H). 103

581.2 (M + NH₄)⁺ Method C, RT = 1.965 min, 100% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.68 (d, J = 1.5 Hz, 1H), 8.22 (t, J = 9.0 Hz, 1H),7.97-7.86 (m, 1H), 7.70-7.56 (m, 2H), 7.45 (dd, J = 11.2, 2.4 Hz, 1H),7.41- 7.29 (m, 2H), 7.29-7.17 (m, 2H), 7.12 (d, J = 9.0 Hz, 1H), 4.62(d, J = 9.0 Hz, 1H), 3.86 (br. d., J = 9.3 Hz, 1H), 3.45 (br. d., J =9.3 Hz, 1H), 1.54 (d, J = 13.2 Hz, 6H), 1.21 (s, 3H), 1.05 (s, 3H). 104

600.2 Method C, RT = 1.871 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.98-8.86 (m, 1H), 8.41 (t, J = 8.68 Hz, 1H), 8.02-7.92 (m, 1H), 7.77-7.60(m, 3H), 7.56-7.48 (m, 1H), 7.46-7.30 (m, 3H), 7.28-7.18 (m, 1H),4.65-4.51 (m, 1H), 3.98-3.81 (m, 2H), 3.81-3.73 (m, 1H), 3.73-3.61 (m,1H), 2.65-2.54 (m, 1H), 2.17-2.02 (m, 1H), 1.44 (d, J = 14.67 Hz, 3H),1.12 (t, J = 7.1 Hz, 3H). 105

600.2 Method C, RT = 1.871 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.02-8.90 (m, 1H), 8.41 (t, J = 8.3 Hz, 1H), 8.05-7.92 (m, 1H), 7.76-7.60 (m,3H), 7.51 (dd, J = 8.7, 1.1 Hz, 1H), 7.46-7.31 (m, 3H), 7.28-7.15 (m,1H), 4.65-4.53 (m, 1H), 3.97-3.74 (m, 3H), 3.74-3.60 (m, 1H), 2.65-2.56(m, 1H), 2.18-2.02 (m, 1H), 1.45 (d, J = 14.43 Hz, 3H), 1.12 (t, J = 7.1Hz, 3H). 106

580.1 Method C, RT = 1.763 min, 94.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(d, J = 2.5 Hz, 1 H) 8.15 (t, J = 8.9 Hz, 1 H), 7.96-7.88 (m, 1 H),7.67-7.64 (m, 2 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.37-7.47 (m, 2 H), 7.27(d, J = 8.8 Hz, 1 H), 7.16- 7.23 (m, 2 H), 4.47-4.64 (m, 1 H), 3.90-4.01 (m, 1H), 3.82-3.90 (m, 1 H), 2.54- 2.62 (m, 1 H), 2.01-2.15 (m, 1H), 1.53 (d, J = 13.2 Hz, 6 H). 107

568.1 Method C, RT = 1.662 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.74(d, J = 1.71 Hz, 1 H), 8.11 (t, J = 8.93 Hz, 1 H), 7.89-8.01 (m, 1 H),7.57- 7.71 (m, 3 H), 7.40-7.40 (m, 1 H), 7.34- 7.48 (m, 1 H), 7.32 (d, J= 8.31 Hz, 1 H), 7.25-7.14 (m, 2 H), 7.04 (t, J = 52.4 Hz, 1H) 4.41-4.55(m, 1 H), 3.89-4.01 (m, 1 H), 3.64-3.71 (m, 1 H), 2.56-2.52 (m, 1 H),2.18-2.31 (m, 1 H), 1.30-1.63 (m, 6 H). 108

602.1 Method C, RT = 1.892 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(d, J = 2.5 Hz, 1 H), 8.41 (t, J = 8.4 Hz, 1 H), 8.0-7.87 (m, 1 H),7.77-7.71 (m, 1 H), 7.69-7.59 (m, 2 H), 7.55-7.49 (m, 1 H), 7.48-7.42(m, 1 H), 7.41-7.27 (m, 2 H), 7.23-7.13 (m, 1 H), 4.65-4.54 (m, 1 H),3.97-3.86 (m, 1 H), 3.82-3.71 (m, 1 H), 3.51 (s, 3H), 3.49 (s, 3H),2.65-2.56 (m, 1H), 2.18-2.02 (m, 1 H). 109

550.2 Method C, RT = 1.650 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(d, J = 2.0 Hz, 1H), 8.14 (t, J = 8.9 Hz, 1 H), 7.99-7.84 (m, 1 H),7.72-7.55 (m, 2 H), 7.37-7.50 (m, 2 H), 7.35-7.25 (m, 2 H), 7.23-7.17(m, 1 H), 7.14 (d, J = 7.1 Hz, 1 H), 4.70-4.58 (m, 1 H), 4.36- 4.23 (m,1 H), 2.36-2.25 (m, 2 H), 1.46 (d, J = 12.4 Hz, 6H), 1.19 (d, J = 6.4Hz, 3 H). 110

599.2 Method C, RT = 1.851 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.96(d, J = 3.18 Hz, 1 H), 8.84 (m, 1 H), 8.46 (t, J = 8.2 Hz, 1 H), 7.87(m, 1H), 7.63- 7.72 (m, 2 H), 7.52 (d, J = 9.5 Hz, 1 H), 7.19-7.39 (m, 3H), 4.65 (d, J = 9.1 Hz, 1 H), 3.88 (d, J = 9.2 Hz, 1 H), 3.45 (d, J =9.2 Hz, 1 H), 1.63 (d, J = 13.2 Hz, 6H), 1.23 (s, 3 H), 1.07 (s, 3 H).111

566.2 Method C, RT = 1.404 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(s, 1H), 8.17 (t, J = 8.8 Hz, 1H), 8.00- 7.88 (m, 1H), 7.70-7.58 (m,2H), 7.49- 7.36 (m, 2H), 7.33-7.13 (m, 4H), 4.93 (t, J = 5.0 Hz, 1H),4.68-4.56 (m, 1H), 4.25- 4.12 (m, 1H), 3.44 (br. t., J = 4.0 Hz, 2H),2.67-2.61 (m, 1H), 1.98-1.85 (m, 1H), 1.64-1.42 (m, 6H). 112

566.2 Method C, RT = 1.425 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.61(s, 1H), 8.14 (t, J = 8.9 Hz, 1H), 7.98- 7.87 (m, 1H), 7.71-7.56 (m,2H), 7.46- 7.36 (m, 2H), 7.36-7.24 (m, 2H), 7.22- 7.15 (m, 1H), 7.09 (d,J = 7.6 Hz, 1H), 5.15-5.05 (m, 1H), 4.76-4.63 (m, 1H), 4.24-4.11 (m,1H), 3.47 (br. d., J = 3.9 Hz, 2H), 2.53 (br. s., 1H), 2.29-2.20 (m,1H), 1.60-1.41 (m, 6H). 113

565.2 Method C, RT = 1.719 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.84(d, J = 4.9 Hz, 1 H), 8.68 (d, J = 2.5 Hz, 1 H), 8.22 (t, J = 8.9 Hz, 1H), 7.87 (ddd, J = 7.8, 4.4, 1.5 Hz, 1 H), 7.67 (ddd, J = 7.8, 4.9, 2.5Hz, 1 H), 7.44 (dd, J = 11.3, 2.5 Hz, 1 H), 7.26-7.38 (m, 2 H), 7.21(ddd, J = 8.9, 2.5, 1.1 Hz, 1 H), 7.00- 7.16 (m, 1 H), 4.62 (d, J = 9.1Hz, 1 H), 3.86 (d, J = 9.1 Hz, 1 H), 3.44 (d, J = 9.1 Hz, 1H), 1.63 (d,J = 13.7 Hz, 6 H), 1.19- 1.28 (m, 3 H), 1.05 (s, 3 H). 114

600.2 Method D, RT = 1.577 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.06-8.51 (br. s., 1H), 8.45-8.36 (m, 1 H), 8.00-7.87 (m, 1 H), 7.71-7.57 (m,3 H), 7.51 (dd, J = 9.17, 1.10 Hz, 1 H), 7.44- 7.11 (m, 4 H), 4.78-4.61(m, 1 H), 4.26- 4.21 (m, 1 H), 3.50-3.40 (m, 3 H), 2.61- 2.53 (m, 1 H),2.33-2.22 (m, 1 H), 1.44- 1.55 (m, 6 H). 115

584.2 Method D, RT = 1.805 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.97-8.85 (m, 1 H), 8.46-8.34 (m, 1 H), 7.99- 7.89 (m, 1 H), 7.70-7.57 (m, 3H), 7.52 (br. d., J = 8.6 Hz, 1 H), 7.46-7.17 (m, 4 H), 4.71-4.57 (m, 1H), 4.34-4.15 (m, 1 H), 2.37-2.30 (m, 1 H), 1.75-1.62 (m, 1H), 1.59-1.39(m, 6 H), 1.19 (d, J = 6.4 Hz, 3 H). 116

584.2 Method D, RT = 1.802 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.92(d, J = 2.7 Hz, 1 H), 8.40 (t, J = 8.3 Hz, 1 H), 7.97-7.89 (m, 1 H),7.71-7.58 (m, 3 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.40 (m, 1 H), 7.36-7.25(m, 3 H), 4.66 (td, J = 9.2, 7.3 Hz, 1 H), 4.35-4.24 (m, 1 H), 2.38-2.24 (m, 2 H), 1.63-1.41 (m, 6 H), 1.20 (d, J = 6.4 Hz, 3 H). 117

558.2 Method C, RT = 1.711 min, 99.4% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.65(br. s., 1 H), 8.18 (t, J = 8.9 Hz, 1 H), 7.96 (m, 1 H), 7.69-7.53 (m, 2H), 7.43 (dd, J = 12.5, 2.5 Hz, 1 H), 7.37-7.26 (m, 2 H), 7.25-7.10 (m,3 H), 4.57 (dt, J = 10.3, 8.1 Hz, 1 H), 3.95-3.65 (m, 2 H), 2.66-2.55(m, 1 H), 2.14-2.03 (m, 1H), 1.80-1.69 (m, 1 H), 1.51-1.30 (m, 6 H),0.98-0.83 (m, 2 H), 0.67-0.43 (m, 2 H). 118

491 Method C, RT = 1.921 min, 99.3% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.63(d, J = 2.1 Hz, 1 H), 8.29 (dd, J = 5.0, 2.1 Hz, 1 H), 8.15 (t, J = 8.8Hz, 1 H), 7.78 (dd, J = 7.3, 2.1 Hz, 1 H), 7.47-7.36 (m, 2 H), 7.35-7.28(m, 1 H), 7.25-7.05 (m, 3 H), 4.62-4.48 (m, 1 H), 3.95-3.84 (m, 1 H),3.89 (s, 3H), 3.83-3.71 (m, 1 H), 2.63-2.52 (m, 1 H), 2.14-2.03 (m, 1H).119

545.1 Method C, RT = 1.737 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.64(d, J = 2.0 Hz, 1H), 8.19-8.05 (m, 1H), 7.63-7.52 (m, 2H), 7.50-7.35 (m,4H), 7.27-7.13 (m, 3H), 4.55 (td, J = 10.5, 8.0 Hz, 1H), 4.30 (t, J =7.9 Hz, 2H), 3.96-3.81 (m, 3H), 3.81-3.72 (m, 1H), 2.61-2.54 (m, 1H),2.13-2.02 (m, 1H). 120

585.0 Method E, RT = 2.500 min, 99.9% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(d, J = 2.7 Hz, 1H), 8.85 (d, J = 4.7 Hz, 1H), 8.40 (t, J = 8.2 Hz, 1H),7.90 (m, 1H), 7.72-7.63 (m, 2H), 7.51 (m, 1H), 7.37-7.28 (m, 3H), 4.67(m, 1H), 4.30 (m, 1H), 2.46-2.23 (m, 2H), 1.62 (d, J = 13.2 Hz, 6H),1.19 (d, J = 5.2 Hz, 3H). 121

551.2 Method C, RT = 1.596 min, 90.1% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.85(d, J = 4.9 Hz, 1H), 8.69-8.60 (m, 1H), 8.20-8.09 (m, 1H), 7.91 (dd, J =6.7, 4.9 Hz, 1H), 7.68 (m, 1H), 7.43 (dd, J = 11.0, 2.5 Hz, 1H),7.37-7.30 (m, 1H), 7.29- 7.18 (m, 3H), 4.69-4.50 (m, 1H), 4.34- 4.10 (m,1H), 2.86-2.76 (m, 1H), 1.65- 1.62 (m, 1H), 1.63 (d, J = 13.4 Hz, 3H),1.62 (d, J = 13.4 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H). 122

551.2 Method C, RT = 1.592 min, 92.5% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.85(d, J = 4.2 Hz, 1 H), 8.65 (s, 1 H), 8.15 (t, J = 8.9 Hz, 1 H), 7.90 (m,1 H), 7.68 (m, 1H), 7.42 (dd, J = 11.1, 2.3 Hz, 1 H), 7.36-7.31 (m, 2H), 7.22-7.14 (m, 2 H), 4.70-4.59 (m, 1 H), 4.34-4.26 (m, 1 H),2.37-2.27 (m, 2 H), 1.62 (d, J = 13.5 Hz, 6 H), 1.12 (d, J = 6.1 Hz,3H). 123

618.2 (M + NH₄)⁺ Method C, RT = 1.502 min, 100% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.91 (d, J = 2.7 Hz, 1H), 8.85 (d, J = 4.6 Hz, 1H), 8.41(t, J = 8.6 Hz, 1H), 7.89 (dd, J = 7.5, 4.0 Hz, 1H), 7.70-7.63 (m, 2H),7.51 (br. d., J = 8.6 Hz, 1H), 7.34 (t, J = 6.4 Hz, 2H), 7.25 (d, J =7.3 Hz, 1H), 5.12 (t, J = 4.9 Hz, 1H), 4.77-4.66 (m, 1H), 4.19 (br. d.,J = 8.3 Hz, 1H), 3.49- 3.43 (m, 2H), 2.62-2.53 (m, 1H), 2.33- 2.22 (m,1H), 1.63 (d, J = 13.4 Hz, 3H), 1.62 (d, J = 13.4 Hz, 3H). 124

600.2 Method C, RT = 1.577 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 9.19(br. s., 1H), 8.45 (t, J = 8.4 Hz, 1H), 7.96- 7.86 (m, 1H), 7.70-7.58(m, 3H), 7.52 (d, J = 8.4 Hz, 1H), 7.42-7.33 (m, 2H), 7.31-7.22 (m, 2H),4.87 (t, J = 8.1 Hz, 1H), 4.18-4.07 (m, 1H), 3.71 (br. d., J = 8.8 Hz,1H), 3.64-3.58 (m, 1H), 3.4- 3.2 (m, 2H), 2.85-2.72 (m, 1H), 1.52 (br.d., J = 13.2 Hz, 6H). 125

583.2 (M + NH₄)⁺ Method D, RT = 1.442 min, 100% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.70- 8.63 (m, 1H), 8.13 (t, J = 8.6 Hz, 1H), 7.97-7.86 (m,1H), 7.71-7.58 (m, 2H), 7.45-7.35 (m, 3H), 7.29-7.17 (m, 3H), 4.37 (dd,J = 10.0, 8.3 Hz, 1H), 3.88- 3.81 (m, 1H), 3.76-3.66 (m, 1H), 3.61 (dd,J = 11.0, 6.6 Hz, 2H), 2.66-2.56 (m, 1H), 1.53 (br. d., J = 13.2 Hz,6H). 126

583.2 (M + NH₄)⁺ Method D, RT = 1.482 min, 94.5% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.90 (s, 1H), 8.19 (t, J = 8.9 Hz, 1H), 7.98- 7.86 (m, 1H),7.69-7.59 (m, 2H), 7.43 (dd, J = 11.2, 2.4 Hz, 1H), 7.40-7.34 (m, 2H),7.30-7.24 (m, 1H), 7.23-7.18 (m, 1H), 7.12 (d, J = 7.8 Hz, 1H), 4.85 (t,J = 8.1 Hz, 1H), 4.17-4.07 (m, 1H), 3.71 (br. d., J = 9.5 Hz, 1H), 3.60(br. dd., J = 9.5, 3.2 Hz, 2H), 2.76-2.70 (m, 1H), 1.52 (br. d., J =13.2 Hz, 6H). 127

583.2 (M + NH₄)⁺ Method D, RT = 1.490 min, 96.5% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.91 (s, 1H), 8.20 (t, J = 9.1 Hz, 1H), 7.98- 7.86 (m, 1H),7.71-7.61 (m, 2H), 7.43 (dd, J = 11.0, 2.5 Hz, 1H), 7.40-7.34 (m, 2H),7.30-7.24 (m, 1H), 7.21-7.16 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 4.86 (t,J = 8.2 Hz, 1H), 4.16-4.08 (m, 1H), 3.72 (br. d., J = 9.3 Hz, 1H), 3.60(br. dd., J = 9.3, 3.2 Hz, 2H), 2.76-2.71 (m, 1H), 1.53 (br. d., J =13.2 Hz, 6H). 128

585.0 Method E, RT = 2.517 min, 99.7% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.93(br. s., 1H), 8.84 (d, J = 3.9 Hz, 1H), 8.41 (t, J = 8.1 Hz, 1H),7.93-7.88 (m, 1H), 7.74-7.61 (m, 2H), 7.51 (br. d., J = 8.3 Hz, 1H),7.44-7.21 (m, 3H), 4.70-4.52 (m, 1H), 4.22 (br. d., J = 9.5 Hz, 1H),2.85-2.78 (m, 1H), 2.57-2.52 (m, 1H), 1.63 (d, J = 13.4 Hz, 3H), 1.61(d, J = 13.4 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H). 129

552.1 Method D, RT = 1.831 min, 100% ¹H NMR (400 MHz, DMSO-d₆) δ = 8.71-8.55 (m, 1H), 8.21-8.09 (m, 2H), 7.91- 7.73 (m, 2H), 7.61-7.50 (m, 1H),7.42 (dd, J = 11.2, 2.0 Hz, 1H), 7.37-7.24 (m, 2H), 7.24-7.11 (m, 2H),4.70-4.52 (m, 1H), 4.39-4.13 (m, 1H), 3.06 (s, 3H), 2.38-2.23 (m, 2H),1.12 (d, J = 6.1 Hz, 3H). 130

548.2 Method C, RT = 1.578 min, 99.6% ¹H NMR (400 MHz, DMSO-d₆) δ =9.73- 9.50 (m, 1H), 8.95 (d, J = 1.2 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H),7.97-7.85 (m, 1H), 7.71-7.56 (m, 2H), 7.43-7.31 (m, 3H), 7.30-7.21 (m,1H), 4.67 (d, J = 9.0 Hz, 1H), 3.89-3.82 (m, 1H), 3.47 (br. d., J = 9.5Hz, 1H), 1.53 (d, J = 13.2 Hz, 6H), 1.23 (s, 3H), 1.07 (s, 3H). 131

669.4 Method D, RT = 1.764 min, 100% 1H NMR (400 MHz, DMSO-d₆) δ = 8.93(d, J = 2.0 Hz, 1H), 8.40 (t, J = 8.6 Hz, 1H), 7.94 (dd, J = 12.6, 7.5Hz, 1H), 7.73- 7.57 (m, 3H), 7.50 (br. d., J = 8.6 Hz, 1H), 7.41-7.17(m, 4H), 4.78-4.66 (m, 1H), 4.47-4.28 (m, 1H), 3.32-3.20 (m, 2H),3.29-3.07 (m, 2H), 2.56-2.48 (m, 2H), 2.46-2.17 (m, 6H), 1.51 (br. d., J= 13.2 Hz, 6H). 132

579.2 (M + NH₄)⁺ Method D, RT = 1.736 min, 100% ¹H NMR (400 MHz,DMSO-d₆) δ = 8.61- 8.54 (m, 1H), 8.14 (t, J = 8.8 Hz, 1H), 7.96-7.88 (m,1H), 7.68-7.59 (m, 2H), 7.44 (dd, J = 11.1, 2.6 Hz, 1H), 7.41- 7.35 (m,2H), 7.30-7.24 (m, 1H), 7.22- 7.18 (m, 1H), 7.09-7.01 (m, 1H), 4.78-4.67 (m, 1H), 4.16-4.05 (m, 1H), 3.62- 3.53 (m, 1H), 1.52 (br. d., J =13.2 Hz, 6H), 0.90-0.71 (m, 4H). 133

524.1 Method E, RT = 1.518 min, 98.9% 1H NMR (400 MHz, DMSO-d₆) δ = 8.99(s, 1H), 7.92 (m, 1H), 7.52-7.72 (m, 2H), 7.33-7.41 (m, 2H), 7.21-7.29(m, 1H), 7.04 (m, 2H), 6.73 (d, J = 7.5 Hz, 1H), 4.53 (m, 1H), 3.83-3.95(m, 1H), 3.71-3.81 (m, 1H), 2.60-2.54 (m, 1H), 2.04-2.19 (m, 1H), 1.52(br. d., J = 13.2 Hz, 6H). 134

518.1 Method D, RT = 1.511 min, 99.1% 135

524.1 Method D, RT = 1.496 min, 95.0%

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

We claim:
 1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: Ar¹ is arylsubstituted with 1-2 R^(1a) and 1-2 R^(1b) or monocyclic heteroaryl with1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, andsubstituted with 1-2 R^(1a) and 1-2 R^(1b); Ar² is aryl substituted with1-4 R^(2a) or 6-membered heteroaryl with 1-2 nitrogen atoms, andsubstituted with 1-4 R^(2a); Ar³ is aryl substituted with 1-4 R^(3a) ormonocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen,oxygen, and sulfur, and substituted with 1-4 R^(3a); R^(1a) is hydrogenor halo; R^(1b) is halo, haloalkyl, alkoxy, or haloalkoxy; R^(2a) ishydrogen, cyano, halo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,alkoxy, or haloalkoxy; alternatively, two adjacent R^(2a) groups aretaken together with the carbon atoms to which they are attached to forma heterocycle with 1-4 heteroatoms selected from nitrogen, oxygen, andsulfur; R^(3a) is cyano, halo, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl,haloalkyl, (R¹R²N)alkyl, R¹R²N, alkylC(O)(R²)Nalkyl, (alkyl)₂(O)P,(alkoxy)₂(O)P, (alkoxy)(alkyl)(O)P, (alkyl)(O)(NR¹)S, alkylSO₂, oralkylSO₂NH; alternatively, two adjacent R^(3a) groups are taken togetherwith the carbon atoms to which they are attached to form a heterocyclewith 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur; R^(4a)or R^(4b) is independently hydrogen, alkyl, alkoxy, hydroxylalkyl,alkoxyalkyl, or haloalkoxy; alternatively, R^(4a) and R^(4b) togetherwith the carbon atom they are both attached to form a C₃₋₆ cycloalkyl;R^(5a) or R^(5b) is independently hydrogen, alkyl, hydroxylalkyl,alkoxyalkyl or haloalkoxyl; R¹ is hydrogen or alkyl; and R² is hydrogenor alkyl; or R¹R²N taken together is azetidinyl, oxazolyl pyrrolidinyl,piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3substituents selected from halo, alkyl, and oxo.
 2. The compound ofclaim 1, having Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: Ar¹ is phenylsubstituted with 1-2 R^(1a) and 1-2 R^(1b) or 6-membered heteroaryl with1-3 nitrogen atoms and substituted with 1R^(1a) and 1-2 R^(1b); Ar³ isphenyl substituted with 1-3 R^(3a) or 5- to 6-membered heteroaryl with1-3 nitrogen atoms and substituted with 1-3 R^(3a); R^(1a) is hydrogenor halo; R^(1b) is halo, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; R^(3a)is cyano, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxyalkyl, C₁₋₄haloalkyl, (R¹R²N)C₁₋₄ alkyl, R¹R²N, C₁₋₄ alkylC(O)(R²)NC₁₋₄ alkyl,(C₁₋₄ alkyl)₂(O)P, (C₁₋₄ alkoxy)₂(O)P, (C₁₋₄ alkoxy)(C₁₋₄ alkyl)(O)P,C₁₋₄ alkylSO₂, or C₁₋₄ alkylSO₂NH; R¹R²N taken together is oxazolyl orpyrrolidinyl and is substituted with 0-3 substituents selected fromhalo, alkyl, and oxo; R^(4a) or R^(4b) is independently hydrogen, C₁₋₄alkyl, or C₁₋₄ hydroxylalkyl; alternatively, R^(4a) and R^(4b) togetherwith the carbon atom they are both attached to form a C₃₋₆ cycloalkyl;and R^(5a) or R^(5b) is independently hydrogen, C₁₋₄ alkyl, C₁₋₄hydroxylalkyl, or C₁₋₄ alkoxyalkyl.
 3. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein: Ar¹ is phenylsubstituted with 1-2 R^(1a) and 1-2 R^(1b), pyridinyl substituted with 1R^(1a) and 1-2 R^(1b), or pyrazinyl substituted with 1R^(1a) and 1-2R^(1b); and Ar³ is phenyl substituted with 1-3 R^(3a), pyrazolylsubstituted with 1-3 R^(3a) pyridinyl substituted with 1-3 R^(3a), orpyrimidinyl substituted with 1-3 R^(3a).
 4. The compound of claim 2,having Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: Ar¹ is phenylsubstituted with 1-2 R^(1a) and 1-2 R^(1b), pyridinyl substituted with 1R^(1a) and 1-2 R^(1b), or pyrazinyl substituted with 1 R^(1a) and 1-2R^(1b); R^(1a) is hydrogen or halo; R^(1b) is halo, C₁₋₄ haloalkyl, C₁₋₄alkoxy, or C₁₋₄ haloalkoxy; R^(2a) is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄haloalkoxy; R^(3a) is cyano, halo, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃alkoxyalkyl, C₁₋₃ haloalkyl, R¹R²N, (C₁₋₃ alkyl)₂(O)P, (C₁₋₃alkoxy)₂(O)P, (C₁₋₃ alkoxy)(C₁₋₃ alkyl)(O)P, C₁₋₃ alkylSO₂, or C₁₋₃alkylSO₂NH; R^(4a) or R^(4b) is independently hydrogen, C₁₋₃ alkyl, orC₁₋₃ hydroxylalkyl; alternatively, R^(4a) and R^(4b) together with thecarbon atom they are both attached to form a C₃₋₆ cycloalkyl; and R^(5a)or R^(5b) is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ hydroxylalkyl, orC₁₋₃ alkoxyalkyl.
 5. The compound of claim 4, having Formula (V):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) ishydrogen or F; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; R^(2a) ishydrogen, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or C₃₋₆ cycloalkyl; R^(3a)is halo, hydroxyalkyl, alkoxyalkyl, (C₁₋₂ alkyl)₂(O)P, (C₁₋₂alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂ alkylSO₂, or C₁₋₂alkylSO₂NH; and R^(3a′) is halo.
 6. The compound of claim 5, or apharmaceutically acceptable salt thereof, wherein: R^(1a) is hydrogen orF; R^(1b) is F, Cl, or CF₃; R^(2a) is hydrogen, F, Cl, isopropyl, CF₃,or cyclopropyl; R^(3a) is (CH₃)₂(O)P, (CH₃CH₂)₂(O)P, (CH₃CH₂O)(CH₃)(O)P,CH₃SO₂, or CH₃SO₂NH; and R^(3a′) is F.
 7. The compound of claim 4,having Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) ishydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; R^(2a)is hydrogen, halo, C₁₋₃ alkyl, or C₃₋₆ cycloalkyl; R^(3a) is (C₁₋₂alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂alkylSO₂, or C₁₋₂ alkylSO₂NH.
 8. The compound of claim 2, having Formula(VII):

or a pharmaceutically acceptable salt thereof, wherein: Ar³ is pyrazolylsubstituted with 1-3 R^(3a), pyridinyl substituted with 1-3 R^(3a), orpyrimidinyl substituted with 1-3 R^(3a); R^(1a) is hydrogen or halo;R^(1b) is halo, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; R^(2a)is hydrogen, halo, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy; R^(3a) is cyano, halo, C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxyalkyl, (R¹R²N)C₁₋₄alkyl, R¹R²N—,(C₁₋₄ alkyl)₂(O)P, (C₁₋₄ alkoxy)₂(O)P, (C₁₋₄ alkoxy)(C₁₋₄ alkyl)(O)P,C₁₋₄ alkylSO₂, or C₁₋₄ alkylSO₂NH; R¹ is hydrogen or alkyl; R² ishydrogen or alkyl; or R¹R²N taken together is oxazolyl or pyrrolidinyl,and is substituted with 0-3 substituents selected from halo, alkyl, oroxo; R^(4a) or R^(4b) is independently hydrogen, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkoxyalkyl, or C₁₋₄ haloalkoxy; R^(4a) and R^(4b) togetherwith the carbon atom they are both attached to form a C₃₋₆ cycloalkyl;and R^(5a) or R^(5b) is independently hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkoxyalkyl, or C₁₋₄ haloalkoxy.
 9. The compound of claim 8, havingFormula (VIII):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) ishydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; R^(2a)is hydrogen, halo, C₁₋₃ alkyl, or C₃₋₆ cycloalkyl; R^(3a) is (C₁₋₂alkyl)₂(O)P, (C₁₋₂ alkoxy)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, C₁₋₂alkylSO₂, or C₁₋₂ alkylSO₂NH; and R^(5a) or R^(5b) is independentlyhydrogen or C₁₋₂ alkyl.
 10. The compound of claim 1, having Formula(IX):

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) ishydrogen or halo; R^(1b) is halo, C₁₋₂ haloalkyl, or C₁₋₂ alkoxy; R^(2a)is hydrogen, halo, C₁₋₂ haloalkyl, C₁₋₃ alkyl, or C₃₋₆ cycloalkyl; Ar³is

R^(3a) is (C₁₋₂ alkyl)₂(O)P, (C₁₋₂ alkoxy)(C₁₋₂ alkyl)(O)P, or C₁₋₂alkylSO₂NH; R^(3a′) is halo; R^(4a) or R^(4b) is independently hydrogen,C₁₋₂ alkyl, or C₁₋₂ hydroxyalkyl; or R^(4a) and R^(4b) together with thecarbon atom to which they are both attached form a C₃₋₆ cycloalkyl; andR^(5a) or R^(5b) is independently hydrogen, C₁₋₂ alkyl, C₁₋₂hydroxyalkyl, or C₁₋₂ alkoxyalkyl.
 11. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein: R^(4a) is hydrogen;R^(4b) is hydrogen; R^(5a) is C₁₋₂ alkyl, C₁₋₂ hydroxylalkyl, or C₁₋₂alkoxyalkyl; and R^(5b) is hydrogen.
 12. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein: R^(4a) is C₁₋₂ alkyl;R^(4b) is C₁₋₂ alkyl; R^(5a) is hydrogen; and R^(5b) is hydrogen.
 13. Acompound of Formula (I):

wherein: Ar¹ is phenyl, pyridinyl, or pyridazinyl and is substitutedwith 1 halo, haloalkyl or haloalkoxy substituent in the 4-position and0-2 additional halo or haloalkyl substituents; Ar² is phenyl orpyridinyl and is substituted with 0-2 substituents selected from cyano,fluoro, alkyl, haloalkyl, cycloalkyl, alkoxy, and haloalkoxy; Ar³ isphenyl or pyridinyl and is substituted with 0-2 substituents selectedfrom cyano, halo, hydroxyalkyl, alkoxyalkyl, (R¹R²N)alkyl, (alkyl)₂(O)P,(alkyl)(O)(NR¹)S, alkylSO₂, and alkylSO₂NH; R¹ is hydrogen or alkyl; andR² is hydrogen or alkyl; or (R¹)(R²)N taken together is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl and issubstituted with 0-3 substituents selected from halo and alkyl; or apharmaceutically acceptable salt thereof.
 14. A compound of claim 13where Ar¹ is phenyl substituted with 1 halo, haloalkyl or haloalkoxysubstituent in the 4-position and 0-2 additional halo or haloalkylsubstituents.
 15. A compound of claim 13 where Ar² is phenyl substitutedwith 0 substituents, 1 alkyl or cycloalkyl substituent, or 1-2 fluorosubstituents.
 16. A compound of claim 13 where Ar³ is phenyl substitutedwith 1-2 substituents selected from cyano, halo, hydroxyalkyl,alkoxyalkyl, (R¹R²N)alkyl, (alkyl)₂(O)P, (alkyl)(O)(NR¹)S, alkylSO₂, andalkylSO₂NH.
 17. A compound of claim 13 where R¹ is hydrogen and R² ishydrogen.
 18. A compound of claim 13 selected from the group consistingof

or a pharmaceutically acceptable salt thereof.
 19. A compound selectedfrom the group consisting of

or a pharmaceutically acceptable salt thereof.
 20. A compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, diluent, orexcipient.
 21. A method for treating a heart disease comprisingadministering a therapeutically effective amount of a compound of claim1 to a patient in need thereof.
 22. The method of claim 21 wherein theheart disease is selected from the group consisting of angina pectoris,unstable angina, myocardial infarction, heart failure, acute coronarydisease, acute heart failure, chronic heart failure, and cardiaciatrogenic damage.
 23. The method of claim 22 wherein the heart failureis selected from the group consisting of congestive heart failure,systolic heart failure, diastolic heart failure, heart failure withreduced ejection fraction (HF_(R)EF), heart failure with preservedejection fraction (HF_(P)EF), acute heart failure, chronic heart failureof ischemic and non-ischemic origin.
 24. A compound, which is


25. A pharmaceutically acceptable salt of


26. A composition comprising the compound of claim 24 and apharmaceutically acceptable carrier, diluent, or excipient.
 27. Acomposition comprising the pharmaceutically acceptable salt of claim 25and a pharmaceutically acceptable carrier, diluent, or excipient.
 28. Amethod for treating heart failure comprising administering to a patientin need thereof a therapeutically effective amount of the compound ofclaim
 24. 29. A method for treating heart failure comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutically acceptable salt of claim
 25. 30. Acompound, which is


31. A pharmaceutically acceptable salt of


32. A composition comprising the compound of claim 30 and apharmaceutically acceptable carrier, diluent, or excipient.
 33. Acomposition comprising the pharmaceutically acceptable salt of claim 31and a pharmaceutically acceptable carrier, diluent, or excipient.
 34. Amethod for treating heart failure comprising administering to a patientin need thereof a therapeutically effective amount of the compound ofclaim
 30. 35. A method for treating heart failure comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutically acceptable salt of claim
 31. 36. Acompound, which is


37. A pharmaceutically acceptable salt of


38. A composition comprising the compound of claim 36 and apharmaceutically acceptable carrier, diluent, or excipient.
 39. Acomposition comprising the pharmaceutically acceptable salt of claim 37and a pharmaceutically acceptable carrier, diluent, or excipient.
 40. Amethod for treating heart failure comprising administering to a patientin need thereof a therapeutically effective amount of the compound ofclaim
 36. 41. A method for treating heart failure comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutically acceptable salt of claim
 37. 42. Acompound, which is


43. A pharmaceutically acceptable salt of


44. A composition comprising the compound of claim 42 and apharmaceutically acceptable carrier, diluent, or excipient.
 45. Acomposition comprising the pharmaceutically acceptable salt of claim 43and a pharmaceutically acceptable carrier, diluent, or excipient.
 46. Amethod for treating heart failure comprising administering to a patientin need thereof a therapeutically effective amount of the compound ofclaim
 42. 47. A method for treating heart failure comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutically acceptable salt of claim
 43. 48. Acompound, which is


49. A pharmaceutically acceptable salt of


50. A composition comprising the compound of claim 48 and apharmaceutically acceptable carrier, diluent, or excipient.
 51. Acomposition comprising the pharmaceutically acceptable salt of claim 49and a pharmaceutically acceptable carrier, diluent, or excipient.
 52. Amethod for treating heart failure comprising administering to a patientin need thereof a therapeutically effective amount of the compound ofclaim
 48. 53. A method for treating heart failure comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutically acceptable salt of claim 49.